Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation

ABSTRACT

The invention relates to polymorphs of zoledronic acid and zoledronate sodium salts, amorphous zoledronate sodium salt, processes for making the polymorphs and amorphous zoledronate sodium salt, and pharmaceutical compositions containing the polymorphs and amorphous zoledronate sodium salt.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.10/886,099, filed Jul. 6, 2004, now abandoned, which claims the benefitof U.S. provisional application Ser. No. 60/484,876, filed Jul. 3, 2003,the contents of all of which is incorporated herein.

FIELD OF THE INVENTION

The invention relates to polymorphs of zoledronic acid and zoledronatesodium salts, amorphous zoledronate sodium salt, processes for makingthe polymorphs and amorphous zoledronate sodium salt and pharmaceuticalcompositions containing the polymorphs and amorphous zoledronate sodiumsalt.

BACKGROUND OF THE INVENTION

Zoledronic acid is a bisphosphonic acid, which is an inhibitor ofosteoclastic bone resorption. Zoledronic acid, designated chemically as(1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid is marketedin the U.S. under the name Zometa® (zoledronic acid for injection).Zometa® is available in vials as a sterile powder for reconstitution forintravenous infusion. The prescribing information for Zometa® statesthat each vial of Zometa® contains 4.264 mg of zoledronic acidmonohydrate (corresponding to 4 mg zoledronic acid on an anhydrousbasis).

U.S. Pat. No. 4,939,130 discloses a method for making substitutedalkanediphosphonic acids. Example 10 describes a method for makingzoledronic acid. In this example, at the end of the reaction, theproduct, which is recrystallized from water, has a melting point of 239°C. with decomposition. However, repetition of the procedure described inExample 10 (which requires stirring under reflux imidazol-1-ylaceticacid hydrochloride and phosphoric acid in chlorobenzene) did not lead tozoledronic acid; instead, the starting material was collected at the endof the reaction. Moreover, the last step of crystallization could not berepeated exactly since the detailed experimental parameters are notgiven (different cooling regimes, for instance, can produce differentpolymorphs when crystallized in the same solvent).

In the paper Drugs of the future 2000, 25(3): 259-268 the followingforms of Zoledronate are listed:

-   -   1) Zoledronic acid disodium salt tetrahydrate CAS No.        165800-07-7    -   2) Zoledronic acid magnesium salt CAS No. 157432-59-2    -   3) Zoledronic acid zinc salt CAS No. 157432-58-1    -   4) Zoledronic acid disodium salt anhydrous CAS No. 131654-46-1    -   5) Zoledronic acid anhydrous CAS No. 118072-93-8    -   6) Zoledronic acid monohydrate CAS No. 165800-06-6

It is also disclosed in the paper that the free acid has a melting pointof 239° C. with decomposition, and the disodium salt dihydrate has amelting point of 291-293° C. with decomposition. However, the paper doesnot describe any procedure to obtain the forms mentioned therein, nordoes it give any additional data by which they can be identified.Moreover, there is nothing in the literature that discloses polymorphsor different crystal forms of zoledronic acid.

The solid state physical properties of a compound can be influenced bycontrolling the conditions under which the compounds are obtained insolid form. Solid state physical properties include, for example, theflowability of the milled solid. Flowability affects the ease with whichthe material is handled during processing into a pharmaceutical product.When particles of the powdered compound do not flow past each othereasily, a formulation specialist must take that fact into account indeveloping a tablet or capsule formulation, which may necessitate theuse of glidants such as colloidal silicon dioxide, talc, starch ortribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid can have therapeuticconsequences since it imposes an upper limit on the rate at which anorally-administered active ingredient can reach the patient'sbloodstream. The rate of dissolution is also a consideration informulating syrups, elixirs and other liquid medicaments. The solidstate form of a compound may also affect its behavior on compaction andits storage stability.

These practical physical characteristics are determined by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. The polymorphicform may give rise to thermal behavior different from that of theamorphous material or another polymorphic form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetry (DSC) and can be used to distinguish some polymorphic formsfrom others. A particular polymorphic form may also give rise todistinct spectroscopic properties that may be detectable by powder X-raydiffraction (PXRD), solid state ¹³C NMR spectrometry and infraredspectrometry.

The discovery of new polymorphic forms of a pharmaceutically usefulcompound provides a new opportunity to improve the performancecharacteristics of a pharmaceutical product. It enlarges the repertoireof materials that a formulation scientist has available for designing,for example, a pharmaceutical dosage form of a drug with a targetedrelease profile or other desired characteristic. The invention providesfor new polymorphic forms of zoledronic acid and zoledronate sodium, andfor amorphous zoledronate sodium.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative PXRD pattern of zoledronic acid Form I.

FIG. 2 is a representative DSC curve of zoledronic acid Form I.

FIG. 3 is a representative PXRD pattern of zoledronic acid Form II.

FIG. 4 is a representative PXRD pattern of zoledronic acid Form XII.

FIG. 5 is a representative PXRD pattern of zoledronic acid Form XV.

FIG. 6 is a representative PXRD pattern of zoledronic acid Form XVIII.

FIG. 7 is a representative PXRD pattern of zoledronic acid Form XX.

FIG. 8 is a representative PXRD pattern of zoledronic acid Form XXVI.

FIG. 9 is a representative PXRD pattern of zoledronate monohydrate FormVIII.

FIG. 10 is a representative PXRD pattern of zoledronate monosodium FormXVI.

FIG. 11 is a representative PXRD pattern of zoledronate monosodium FormXVII.

FIG. 12 is a representative PXRD pattern of zoledronate disodium Form V.

FIG. 13 is a representative PXRD pattern of zoledronate disodium FormVI.

FIG. 14 is a representative PXRD pattern of zoledronate disodium FormVII.

FIG. 15 is a representative PXRD pattern of zoledronate disodium Form X.

FIG. 16 is a representative PXRD pattern of zoledronate disodium FormXIII.

FIG. 17 is a representative PXRD pattern of zoledronate disodium FormXIV.

FIG. 18 is a representative PXRD pattern of zoledronate disodium FormXIX.

FIG. 19 is a representative PXRD pattern of zoledronate disodium FormXXV.

FIG. 20 is a representative PXRD pattern of zoledronate disodium FormXXVII.

FIG. 21 is a representative PXRD pattern of zoledronate disodium FormIX.

FIG. 22 is a representative PXRD pattern of zoledronate disodium FormXI.

FIG. 23 is a representative PXRD pattern of zoledronate sodiumamorphous.

FIG. 24 is a representative TGA curve of zoledronic acid Form I.

FIG. 25 is a representative TGA curve of zoledronic acid Form II.

FIG. 26 is a representative TGA curve of zoledronic acid Form XII.

FIG. 27 is a representative TGA curve of zoledronic acid Form XV.

FIG. 28 is a representative TGA curve of zoledronic acid Form XVIII.

FIG. 29 is a representative TGA curve of zoledronic acid Form XX.

FIG. 30 is a representative TGA curve of zoledronic acid Form XXVI.

FIG. 31 is a representative TGA curve of zoledronate monosodium FormVIII.

FIG. 32 is a representative TGA curve of zoledronate monosodium FormXVI.

FIG. 33 is a representative TGA curve of zoledronate monosodium FormXVII.

FIG. 34 is a representative TGA curve of zoledronate disodium Form V.

FIG. 35 is a representative TGA curve of zoledronate disodium Form VI.

FIG. 36 is a representative TGA curve of zoledronate disodium Form VII.

FIG. 37 is a representative TGA curve of zoledronate disodium Form X.

FIG. 38 is a representative TGA curve of zoledronate disodium Form XIII.

FIG. 39 is a representative TGA curve of zoledronate disodium Form XIV.

FIG. 40 is a representative TGA curve of zoledronate disodium Form XIX.

FIG. 41 is a representative TGA curve of zoledronate disodium Form XXV.

FIG. 42 is a representative TGA curve of zoledronate disodium FormXXVII.

FIG. 43 is a representative TGA curve of zoledronate disodium Form IX.

FIG. 44 is a representative TGA curve of zoledronate disodium Form XI.

SUMMARY OF THE INVENTION

The invention relates to polymorphs of zoledronic acid and zoledronatesodium salts, amorphous zoledronate sodium salt, processes for makingthe polymorphs and amorphous zoledronate sodium salt and pharmaceuticalcompositions containing the polymorphs and amorphous zoledronate sodiumsalt. The invention can be understood by reference to the followingnumbered embodiments.

1. Crystalline solid zoledronic acid (Form I) characterized by a powderX-ray diffraction pattern having peaks at 12.1°, 12.8°, 15.7°, and 18.9°2θ±0.2° 2θ.

2. The crystalline solid zoledronic acid of embodiment 1, furthercharacterized by a powder XRD pattern with peaks at 20.9°, 21.3°, 21.8°,22.2°, 25.8°, 27.6°, 29.2°, 32.5°, and 32.9° 2θ±0.2° 2θ.

3. The crystalline solid zoledronic acid of embodiment 1, which containsless than about 5% of other polymorphic forms of zoledronic acid.

4. The crystalline solid zoledronic acid of embodiment 1, of which nomore than about 5% transforms to zoledronic acid Form II upon exposureto 100% relative humidity (RH) for 7 days.

5. The crystalline solid zoledronic acid of embodiment 4, of which nomore than about 5% transforms to other polymorphic forms of zoledronicacid upon exposure to 100% relative humidity (RH) for 7 days.

6. The crystalline solid zoledronic acid of embodiment 1, which, uponexposure to 100% relative humidity (RH) for 7 days, absorbs less thanabout 0.2% water.

7. The crystalline solid zoledronic acid of embodiment 1, which, uponexposure to 100% relative humidity (RH) for 7 days, retains its X-raydiffraction pattern substantially as shown in figure no. 1.

8. The crystalline solid zoledronic acid of embodiment 1, of which nomore than about 5% transforms to zoledronic acid form II upon exposureto 75% relative humidity (RH) at 40° C. for 3 months.

9. The crystalline solid zoledronic acid of embodiment 8, of which nomore than about 5% transforms to other polymorphic forms of zoledronicacid upon exposure to 75% relative humidity (RH) at 40° C. for 3 months.

10. The crystalline solid zoledronic acid of embodiment 1, which, uponexposure to 75% relative humidity (RH) at 40° C. for 3 months, absorbsless than about 0.2% water.

11. The crystalline solid zoledronic acid of embodiment 1, which, uponexposure to 75% relative humidity (RH) at 40° C. for 3 months, retainsits X-ray diffraction pattern substantially as shown in figure no. 1.

12. A pharmaceutical composition comprising the crystalline zoledronicacid of any of embodiments 1 to 11.

13. The crystalline solid zoledronic acid of embodiment 1, which is amonohydrate.

14. Crystalline solid zoledronic acid (Form II) characterized by apowder X-ray diffraction pattern having peaks at 14.6°, 15.4°, 19.1°,22.9°, and 23.9° 2θ±0.2° 2θ.

15. The crystalline zoledronic acid of embodiment 14, furthercharacterized by a powder X-ray diffraction pattern with peaks at 20.8°,21.7°, 25.1°, 26.7°, 29.5°, and 29.9° 2θ±0.2° 2θ.

16. The crystalline solid zoledronic acid of embodiment 14, which is amonohydrate.

17. Crystalline solid zoledronic acid (Form XII) characterized by apowder X-ray pattern having peaks at 9.0°, 13.9°, 14.8°, 21.5°, 24.7°,and 29.8° 2θ±0.2° 2θ.

18. The crystalline zoledronic acid of embodiment 17, furthercharacterized by a powder X-ray diffraction pattern with peaks at 17.0°,20.6°, 20.8°, 22.4°, 25.8°, 27.7°, 28.4°, 28.7°, 29.1°, 30.8°, 31.9°,32.3°, and 32.9° 2θ±0.2° 2θ.

19. The crystalline solid zoledronic acid of embodiment 17, which is amonohydrate.

20. Crystalline solid zoledronic acid (Form XV) characterized by apowder X-ray diffraction pattern having peaks at 10.1°, 17.3°, 19.3°,and 23.2° 2θ±0.2° 2θ.

21. The crystalline zoledronic acid of embodiment 2, furthercharacterized by a powder X-ray diffraction pattern with peaks at 14.5°,16.7°, 18.1°, 24.5°, 25.1°, 25.7°, 28.5°, 29.1°, 29.6°, and 30.4°2θ±0.2° 2θ.

22. The crystalline solid zoledronic acid of embodiment 20, which isanhydrous.

23. Crystalline solid zoledronic acid (Form XVIII) characterized by apowder X-ray diffraction pattern having peaks at 10.7°, 13.0°, 16.4°,17.4°, and 28.5° 2θ±0.2° 2θ.

24. The crystalline zoledronic acid of embodiment 23, furthercharacterized by a powder X-ray diffraction pattern with peaks at 13.3°,18.1°, 19.3°, 21.3°, 23.7°, 25.9°, 31.5°, and 34.5° 2θ±0.2° 2θ.

25. The crystalline solid zoledronic acid of embodiment 23, which is amonohydrate.

26. Crystalline solid zoledronic acid (Form XX) characterized by apowder X-ray diffraction pattern having peaks at 12.2°, 19.3°, 20.2°,21.3°, 25.1°, and 27.25° 2θ±0.2° 2θ.

27. The crystalline zoledronic acid of embodiment 26, furthercharacterized by a powder X-ray diffraction pattern with peaks at 11.4°,14.9°, 15.5°, 17.2°, 18.2°, and 30.5° 2θ±0.2° 2θ.

28. The crystalline solid zoledronic acid of embodiment 26, which isanhydrous.

29. Crystalline solid zoledronic acid (Form XXVI) characterized by apowder X-ray diffraction pattern having peaks at 9.8°, 14.5°, 17.1°,17.6°, and 18.3° 2θ±0.2° 2θ.

30. The crystalline zoledronic acid of embodiment 29, furthercharacterized by a powder X-ray diffraction pattern with peaks at 18.8°,19.7°, 21.4°, 25.7°, 26.6°, and 28.1° 2θ±0.2° 2θ.

31. The crystalline solid zoledronic acid of embodiment 29, which isanhydrous.

32. A pharmaceutical composition comprising the crystalline solidzoledronic acid of any of embodiments 12 to 31.

33. Crystalline solid zoledronate monosodium.

34. Crystalline solid zoledronate monosodium hydrate.

35. The crystalline solid zoledronate monosodium of embodiment 33,characterized by a powder X-ray diffraction pattern having peaks at8.2°, 15.5°, 18.6°, 23.6°, and 26.8° 2θ±0.2° 2θ (Form VIII).

36. The crystalline solid zoledronate monosodium of embodiment 35,further characterized by a powder X-ray diffraction pattern with peaksat 11.8°, 17.6°, 20.1°, 24.7°, 25.0°, 28.4°, 31.7°, and 32.8° 2θ±0.2°2θ.

37. The crystalline solid zoledronate monosodium of embodiment 35, whichis a trihydrate.

38. The crystalline solid zoledronate monosodium of embodiment 33,characterized by a powder X-ray diffraction pattern having peaks at7.3°, 8.8°, 14.7°, 21.8°, and 29.6° 2θ±0.2° 2θ (form XVI).

39. The crystalline solid zoledronate monosodium of embodiment 38,further characterized by a powder X-ray diffraction pattern with peaksat 13.8°, 16.8°, 20.4°, 21.4°, 24.4°, 25.6°, 27.5°, 28.2°, and 31.7°2θ±0.2° 2θ.

40. The crystalline solid zoledronate monosodium of embodiment 38, whichis a dihydrate.

41. The crystalline solid zoledronate monosodium of embodiment 33,characterized by a powder X-ray diffraction pattern having peaks at8.2°, 9.0°, 14.5°, 21.4°, 24.5°, and 29.2° 2θ±0.2° 2θ (Form XVII).

42. The crystalline solid zoledronate monosodium of embodiment 41,further characterized by a powder X-ray diffraction pattern with peaksat 13.9°, 15.5°, 16.8°, 18.6°, 22.3°, 23.6°, 26.7°, 27.7°, and 32.3°2θ±0.2° 2θ.

43. The crystalline solid zoledronate monosodium of embodiment 41, whichis a dihydrate.

44. Crystalline solid zoledronate disodium.

45. Crystalline solid zoledronate disodium hydrate.

46. Crystalline solid zoledronate disodium anhydrous.

47. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having at 11.3°,14.8°, 15.5°, 17.4°, and 19.9° 2θ±0.2° 2θ (Form V).

48. The crystalline solid zoledronate disodium of embodiment 47, furthercharacterized by a powder X-ray diffraction pattern with peaks at 18.0°,18.9°, 19.7°, 22.7°, 25.0°, 26.7°, 30.9°, and 34.5° 2θ±0.2° 2θ.

49. The crystalline solid zoledronate disodium of embodiment 47, whichis a dihydrate.

50. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at7.2°, 13.3°, 13.7°, 14.5°, and 21.7° 2θ±0.2° 2θ (Form VI).

51. The crystalline solid zoledronate disodium of embodiment 50, furthercharacterized by a powder X-ray diffraction pattern with peaks at 8.2°,16.6°, 16.9°, 17.3°, 25.9°, 26.6°, 30.7°, 31.9°, and 32.9° 2θ±0.2° 2θ.

52. The crystalline solid zoledronate disodium of embodiment 50, whichis a trihydrate.

53. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at6.2°, 11.6°, 12.6°, and 13.7 2θ°±0.2° 2θ (Form VII).

54. The crystalline solid zoledronate disodium of embodiment 53, furthercharacterized by a powder X-ray diffraction pattern with peaks at 22.0°,23.2°, 26.4°, 27.1°, 28.6°, 28.8°, and 34.2° 2θ±0.2° 2θ.

55. The crystalline solid zoledronate disodium of embodiment 53, whichis a tetrahydrate.

56. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at6.7°, 14.4°, 18.2°, 20.4°, and 20.7° 2θ±0.2° 2θ (Form X).

57. The crystalline solid zoledronate disodium of embodiment 56, furthercharacterized by a powder X-ray diffraction pattern with peaks at 8.8°,13.7°, 17.0°, 19.8°, 21.3°, 24.4°, 27.5°, 27.9°, 30.9°, and 33.4°2θ±0.2° 2θ.

58. The crystalline solid zoledronate disodium of embodiment 56, whichis a hemihydrate.

59. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at6.5°, 13.0°, 16.1°, 17.2°, and 30.7° 2θ±0.2° 2θ (Form XIII).

60. The crystalline solid zoledronate disodium of embodiment 59, furthercharacterized by a powder X-ray diffraction pattern with peaks at 10.2°,19.0°, 20.0°, 20.6°, 22.3°, 27.4°, 28.6°, 28.9°, and 34.8° 2θ±0.2° 2θ.

61. The crystalline solid zoledronate disodium of embodiment 59, whichis a hemihydrate.

62. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at6.6°, 19.9°, 28.5°, and 34.8° 2θ±0.2° 2θ (Form XIV).

63. The crystalline solid zoledronate disodium of embodiment 62, furthercharacterized by a powder X-ray diffraction pattern with peaks at 13.0°,15.1°, 17.1°, 20.5°, 27.7°, 29.6°, 30.7°, and 33.5° 2θ±0.2° 2θ.

64. The crystalline solid zoledronate disodium of embodiment 62, whichis anhydrous.

65. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at11.6°, 12.5°, 13.7°, 22.0°, and 23.1 ° 2θ±0.2° 2θ (Form XIX).

66. The crystalline solid zoledronate disodium of embodiment 65, furthercharacterized by a powder X-ray diffraction pattern with peaks at 6.2°,14.3°, 15.3°, 16.0°, 18.5°, 24.3°, and 28.6° 2θ±0.2° 2θ.

67. The crystalline solid zoledronate disodium of embodiment 65, whichis a pentahydrate.

68. The crystalline solid zoledronate disodium of embodiment 44,characterized by a powder X-ray diffraction pattern having peaks at7.4°, 13.7°, 17.6°, and 21.9° 2θ±0.2° 2θ (Form XXV).

69. The crystalline solid zoledronate disodium of embodiment 68, furthercharacterized by a powder X-ray diffraction pattern with peaks at 6.3°,9.5°, 12.6°, 14.6°, 26.2°, 27.1°, and 28.6° 2θ±0.2° 2θ.

70. The crystalline solid zoledronate disodium of embodiment 68, whichis a sesquihydrate.

71. The crystalline solid zoledronate disodium of embodiment 44, whichis a monohydrate characterized by a powder X-ray diffraction patternhaving peaks at 6.4°, 8.2°, 16.0°, 17.4°, 19.0°, and 28.8° 2θ±0.2° 2θ(Form XXVII).

72. The crystalline solid zoledronate disodium of embodiment 71, furthercharacterized by a powder X-ray diffraction pattern with peaks at 7.7°,10.2°, 17.2°, 18.1°, 21.6°, 25.7°, and 25.9° 2θ±0.2° 2θ.

73. The crystalline solid zoledronate disodium of embodiment 71, whichis a monohydrate.

74. Crystalline solid zoledronate trisodium.

75. The crystalline solid zoledronate trisodium of embodiment 74,characterized by a powder X-ray diffraction pattern having peaks at8.3°, 10.9°, 15.0°, 16.6°, and 22.8° 2θ±0.2° 2θ (Form IX).

76. The crystalline solid zoledronate trisodium of embodiment 75,further characterized by a powder X-ray diffraction pattern with peaksat 13.1°, 20.2°, 20.6°, 20.9°, 25.0°, 27.8°, and 29.0° 2θ±0.2° 2θ.

77. The crystalline solid zoledronate trisodium of embodiment 75, whichis a trihydrate.

78. The crystalline solid zoledronate trisodium of embodiment 74,characterized by a powder X-ray diffraction pattern having peaks at6.2°, 7.9°, 8.8°, 10.6°, and 12.2° 2θ±0.2° 2θ (Form XI).

79. The crystalline solid zoledronate trisodium of embodiment 78,further characterized by a powder X-ray diffraction pattern with peaksat 15.0°, 15.4°, 17.5°, 18.8°, 19.6°, 20.5°, 22.3°, 23.7°, 25.7°, 29.6°,and 31.7° 2θ±0.2° 2θ.

80. The crystalline solid zoledronate trisodium of embodiment 78, whichis a dihydrate.

81. A process for preparing a solid crystalline zoledronate sodium saltcomprising:

a) dissolving zoledronic acid in water to form a solution;

b) adding a base, preferably sodium hydroxide, to the solution; and

c) cooling the solution, optionally with the addition of an organicsolvent such as isopropyl alcohol, to precipitate crystallinezoledronate sodium.

82. The process of embodiment 81, wherein the crystalline solidzoledronate sodium salt is the monosodium salt.

83. The process of embodiment 82, wherein the crystalline solidzoledronate monosodium is selected from the group consisting of FormVIII, Form XVI and Form XVII.

84. The process of embodiment 81, wherein the crystalline solidzoledronate sodium salt is the disodium salt.

85. The process of embodiment 84, wherein the crystalline solidzoledronate disodium is selected from the group consisting of Form V,Form VI, Form VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, andForm XXVII.

86. The process of embodiment 81, wherein the crystalline solidzoledronate sodium salt is the trisodium salt.

87. The process of embodiment 86, wherein the crystalline solidzoledronate trisodium is selected from the group consisting of Form IXand Form XI.

88. A process for preparing a crystalline solid zoledronate sodium saltcomprising:

a) suspending zoledronic acid in a mixture of alcohol/water, preferablyat reflux temperature

b) adding to the suspension of a) a solution of a base, preferablysodium hydroxide, in an equivalent mixture of alcohol/water as that usedin the suspension of a), to form a reaction mixture; and

c) stirring the reaction mixture for a time sufficient to precipitate acrystalline solid zoledronate sodium salt.

89. The process of embodiment 88, wherein the reaction mixture isstirred at reflux for about 10 to about 20 hours, preferably about14-16.

90. The process of embodiment 88, wherein the volume ratio ofalcohol/water to zoledronic acid in a) and b) is 6-14 volumes,preferably 10 volumes.

91. The process of embodiment 88, wherein the alcohol in a) and b) isselected from the group consisting of methanol, ethanol, isopropanol anddimethylformamide.

92. The process of embodiment 88, wherein the zoledronic acid iszoledronic acid Form I and the ratio of acid to base is 1:1.

93. The process of embodiment 88, wherein the zoledronic acid iszoledronic acid Form I and the ratio of acid to base is 1:2.

94. The process of embodiment 88, wherein the zoledronic acid iszoledronic acid Form XII and the ratio of acid to base is 1:1.1.

95. The process of embodiment 92, wherein the crystalline solidzoledronate sodium salt is the monosodium salt.

96. The process of embodiment 95, wherein the crystalline solidzoledronate monosodium is selected from the group consisting of FormVIII, Form XVI and Form XVII.

97. The process of embodiment 93 or embodiment 94, wherein thecrystalline solid zoledronate sodium salt is the disodium salt.

98. The process of embodiment 97, wherein the crystalline solidzoledronate disodium is selected from the group consisting of Form V,Form VI, Form VII, Form X, Form XIII, Form XIV, Form XIX, Form XXV, andForm XXVII.

99. The process of embodiment 0, wherein the zoledronic acid iszoledronic acid Form XII and the ratio of acid to base is 1:2.1.

100. The process of embodiment 99, wherein the crystalline solidzoledronate sodium salt is the trisodium salt.

101. The process of embodiment 100, wherein the crystalline solidzoledronate trisodium is selected from the group consisting of Form IXand Form XI.

102. A process for preparing a solid crystalline zoledronate sodium saltcomprising:

a) dissolving a crystal form of zoledronate sodium in water, preferablyat reflux, to form a solution; and

b) cooling the solution to precipitate a crystal form of zoledronatesodium which is different from the starting form in a).

103. The process of embodiment 102, wherein the water is added in anamount of between 20-30 volumes, preferably 25 volumes, per volume ofzoledronate sodium.

104. A process for preparing crystalline solid zoledronate monosodiumForm VIII comprising:

a) adding a solution of a base in an 80%/20% v/v mixture ofwater/ethanol to a suspension of zoledronic acid form I in an 80%/20%v/v mixture of water/ethanol at elevated temperature, preferably refluxtemperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form VIII.

105. The process of embodiment 104, wherein the base is sodiumhydroxide, which is added in an amount of a 1:1 molar ratio to thezoledronic acid.

106. The process of embodiment 104, wherein the volume ratio ofwater/ethanol to zoledronic acid form I in the suspension and thesolution is between 6 and 14, preferably 10.

107. A process for preparing crystalline solid zoledronate monosodiumForm VIII comprising:

a) adding a solution of a base in an 80%/20% v/v mixture ofwater/methanol to a suspension of zoledronic acid form I in an 80%/20%v/v mixture of water/methanol at elevated temperature, preferably refluxtemperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form VIII.

108. The process of embodiment 107, wherein the base is sodiumhydroxide, which is added in an amount of a 1:1 molar ratio to thezoledronic acid.

109. The process of embodiment 107, wherein the volume ratio ofwater/methanol to zoledronic acid form I in the suspension and thesolution is between 6-14, preferably 10.

110. A process for preparing crystalline solid zoledronate monosodiumForm VIII comprising:

a) adding a solution of a base in an 60%/40% v/v mixture ofwater/isopropanol to a suspension of zoledronic acid form I in an60%/40% v/v mixture of water/isopropanol at elevated temperature,preferably reflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form VIII.

111. The process of embodiment 110, wherein the base is sodiumhydroxide, which is added in an amount of a 1:1 molar ratio to thezoledronic acid.

112. The process of embodiment 110, wherein the volume ratio ofwater/isopropanol to zoledronic acid form I in the suspension and thesolution is between 6 and 14, preferably 10.

113. A process for preparing crystalline solid zoledronate monosodiumForm XVI comprising:

a) adding a solution of a base in a 50%/o/50% v/v mixture ofwater/ethanol to a suspension of zoledronic acid form I in a 50%/50% v/vmixture of water/ethanol at elevated temperature, preferably refluxtemperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20hours, preferably 14-16 hours; and

c) precipitating zoledronate monosodium Form XVI.

114. The process of embodiment 113, wherein the base is sodiumhydroxide, which is added in an amount of a 1:1 molar ratio to thezoledronic acid.

115. The process of embodiment 113, wherein the volume ratio ofwater/ethanol to zoledronic acid form I in the suspension and thesolution is between 6 and 14, preferably 10.

116. A process for preparing crystalline solid zoledronate monosodiumForm XVI comprising:

a) adding a solution of a base in a 50%/50% v/v mixture ofwater/isopropanol to a suspension of zoledronic acid Form I in a 50%/50%v/v mixture of water/isopropanol at elevated temperature, preferablyreflux temperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20hours, preferably 14 to 16 hours; and

c) precipitating zoledronate monosodium Form XVI.

117. The process of embodiment 116, wherein the base is sodiumhydroxide, which is added in an amount of a 1:1 molar ratio to thezoledronic acid.

118. The process of embodiment 116, wherein the volume ratio ofwater/isopropanol to zoledronic acid form I in the suspension and thesolution is between 6 and 14, preferably 10.

119. A process for preparing crystalline solid zoledronate monosodiumForm XVI comprising:

a) adding a solution of a base in a 50%/50% v/v mixture ofwater/methanol to a suspension of zoledronic acid form I in a 50%/50%v/v mixture of water/ethanol at elevated temperature, preferably refluxtemperature;

b) stirring the mixture of a) at reflux temperature for about 10 to 20hours, preferably 14 to 16 hours; and

c) precipitating zoledronate monosodium Form XVI.

120. The process of embodiment 119, wherein the base is sodiumhydroxide, which is added in an amount of a 1:1 molar ratio to thezoledronic acid.

121. The process of embodiment 119, wherein the volume ratio ofwater/methanol to zoledronic acid form I in the solution is between 6and 14, preferably 10, and the volume ratio of water/ethanol in thesuspension is between 6 and 14, preferably 10.

122. A process for preparing solid crystalline zoledronate sodium FormXVII comprising:

-   -   a) dissolving zoledronic acid Form I in water to form a        solution;    -   b) adding a base, preferably sodium hydroxide, to the solution;        and    -   c) cooling the solution, optionally with the addition of an        organic solvent, to precipitate crystalline zoledronate sodium        Form XVII.

123. A pharmaceutical composition comprising the crystalline solidzoledronate monosodium of any of embodiments 35 to 43.

124. A pharmaceutical composition comprising the crystalline solidzoledronate disodium of any of embodiments 47 to 73.

125. A pharmaceutical composition comprising the crystalline solidzoledronate trisodium of any of embodiments 75 to 80.

126. Amorphous monosodium zoledronate.

127. Amorphous disodium zoledronate.

128. Amorphous trisodium zoledronate.

129. A pharmaceutical composition comprising the amorphous solidzoledronate of any of embodiments 126, 127 and 128.

130. A process for preparing zoledronate amorphous sodium comprising:treating zoledronic acid and a base, preferably sodium hydroxide, inwater at room temperature and precipitating zoledronate amorphoussodium.

131. The process of embodiment 130, wherein the ratio of acid:base is1:1.1.

132. The process of embodiment 130, wherein the ratio of acid:base is1:2.1.

DETAILED DESCRIPTION OF THE INVENTION

Powder X-ray diffraction (“PXRD”) analysis was performed on a ScintagX-Ray powder diffractometer model X'TRA equipped with a solid statedetector. Copper radiation of 1.5418 Å was used. A round aluminum sampleholder with round zero background quartz plate, with a cavity of 25 mmdiameter and 0.5 mm depth, was used.

Loss on drying (“LOD”) was measured by Thermal Gravimetric Analysis(“TGA”) using a Mettler TG50. The sample size was about 9-15 mg. Thesamples were scanned at a rate of 10° C./min from 25° C. to 250° C. Theoven was constantly purged with nitrogen gas at a flow rate of 40ml/min. Standard alumina crucibles covered by lids with one hole wereused.

DSC analysis was done using a Mettler 821 Star^(e). The weight of thesamples was about 3 mg. The samples were scanned at a rate of 10° C./minfrom 30° C. to 300° C. The oven was constantly purged with nitrogen gasat a flow rate of 40 ml/min. Standard 40 ml aluminum crucibles coveredby lids with three holes were used.

Applicants have discovered that different crystal forms of Zoledronicacid may be obtained. Different forms of the zoledronic acid may haveimproved properties with regards to dissolution (since the dosage formis for injection, the material needs to be reconstituted in water;faster dissolution rate would mean faster reconstitution). Therecrystallization of Zoledronic acid leads to a material with a purityof at least 99.5% area by HPLC.

The novel forms of zoledronic acid are hydrated. The level of water inZoledronic acid is estimated by TGA the (thermogravimetric analysis)weight loss.

Zoledronic acid can be found in the anhydrous state (weight loss up to2%), monohydrate (weight loss 5-8%), sesquihydrate (weight loss 9-11%).

A typical DSC scan of zoledronic acid shows an endothermic peak belowabout 160-170° C. due mainly to water desorption, and a subsequentendotherm at about 200° C. concomitant to an exotherm reaction (see FIG.2). From this DSC scan there is no clear detection of a melting point.

Zoledronic Acid Form I

In a first aspect, the invention provides a novel crystalline solid formof Zoledronic acid that has been denominated Form I. Zoledronic acidForm I identified by its PXRD pattern, a representative example of whichis provided in the diffractogram of FIG. 1. Particular characteristicpeaks occur at 12.1, 12.8, 15.7, and 18.9±0.2° 2θ. Additional peaksoccur at 20.9, 21.3, 21.8, 22.2, 25.8, 27.6, 29.2, 32.5, and 32.9±0.2°2θ. The hydration level of Zoledronic acid Form I is indicated by a LODof 5% to 8% (monohydrate) on heating from about 25-220° C.

Zoledronic acid Form I is substantially free of Zoledronic acid Form II.In addition, Zoledronic acid Form I is substantially free of otherpolymorphic forms of Zoledronic acid. Substantially free means less thanabout 5%. A suitable method for detecting other phases and mixtures ofpolymorphs is the X-Ray powder diffraction method (see “Polymorphism inmolecular crystals”, Joel Bernstein, Oxford Science Publications, or“Polymorphism in pharmaceutical solids” edited by Harry G. Brittain).

Zoledronic acid Form I is physically stable and does not substantiallytransform to any other crystal form when exposed to 100% relativehumidity (RH) or less, for one week, or stored at 40° C. and 75% RH for3 months. After exposure to 100% RH or less, for one week, there is nosignificant gain of moisture in Form I (not significant means that itabsorbs less than about 0.2% water). “Substantially transforms to anyother crystal form” means that more than about 5% of the crystal formconverts or rearranges to Form II or any other crystal form.

Accordingly in one embodiment, the invention provides a pharmaceuticalcomposition comprising zoledronic acid Form I substantially free ofother polymorphic forms of zoledronic acid and at least onepharmaceutically acceptable excipient. Preferably the pharmaceuticalcomposition is in the form of an oral solid dosage form.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising zoledronic acid Form I, which is physicallystable and does not substantially transform to any other crystal formwhen stored at 40° C. and 75% RH for 3 months, and at least onepharmaceutically acceptable excipient. Preferably the pharmaceuticalcomposition is in the form of an oral solid dosage form.

The novel crystal forms of Zoledronic acid preferably have a particlesize distribution such that 100% of the particles have a size below 100microns, preferably below 50 microns.

Accordingly, another aspect of the invention is a pharmaceuticalcomposition comprising a novel crystal form of zoledronic acid, whichhas a particle size distribution such that 100% is below 100 microns,preferably below 50 microns, and at least one pharmaceuticallyacceptable excipient.

Zoledronic acid Form I can be prepared by a phosphorylation reaction of1-Imidazoleacetic acid (IAA) in the presence of Phosphorous acid andPhosphorous oxychloride in a diluent, such as, Toluene, Chlorobenzene,PEG-400 and Silicon oil. Phosphorous oxychloride is added to a mixtureof Phosphorous acid and IAA at 75° C. to 80° C. The reaction mixture isthen stirred at 80° C.-100° C., preferably at 80° C. for 1-34 hours,preferably 5-25 hours. Then water is added at 80° C.-100° C. and theaqueous phase is separated. Hydrolysis occurs in about 10-20 hrs,preferably 14-16 hours. At the end of hydrolysis, a solvent like ethanolor acetone may be added to obtain a precipitate of ZLD-Ac after stirringat 5° C. for 1-6 hours, preferably 2.5-4 hours.

Zoledronic Acid Form II

In a second aspect, the invention provides a novel crystalline solidform of Zoledronic acid that has been denominated Form II. Zoledronicacid Form II can be identified by its PXRD pattern, a representativeexample of which is provided in the diffractogram of FIG. 3. Particularcharacteristic peaks occur at 14.6°, 15.4°, 19.1°, 22.9°, and 23.9°2θ±0.2° 2θ. Additional peaks occur at 20.8°, 21.7°, 25.1°, 26.7°, 29.5°,and 29.9° 2θ±0.2° 2θ. The hydration level of Zoledronic acid Form II isindicated by a LOD of about 5% (monohydrate) on heating from about25-220° C.

Form II can be prepared by a phosphorylation reaction of1-Imidazoleacetic acid (IAA, 1 eq.) in the presence of Phosphorous acid(2 eq.) and Phosphorous oxychloride (.NET.) in silicon oil as a diluent.Phosphorous oxychloride is added to a mixture of phosphorous acid andIAA at 75° C. The reaction mixture is then heated to 80° C. for about 27hours. Then water is added at 80° C. and the aqueous phase is separated.Hydrolysis usually occurs within about 10-20 hrs, preferably 14-16hours. At the end of hydrolysis, ethanol is added to obtain aprecipitate of ZLD-Ac after stirring at 5° C. for 1-6 hours, preferably2.5-4 hours.

Zoledronic acid Form II can also be prepared by treating Zoledronic acidform I in Toluene, preferably at reflux temperature, for a duration of5-20 hours, most preferably 10-16 hours.

Zoledronic Acid Form XI

In a third aspect, the invention provides a novel crystalline solid formof Zoledronic acid that has been denominated Form XII. Zoledronic acidForm XII can be identified by its PXRD pattern, a representative exampleof which is provided in the diffractogram of FIG. 4. Particularcharacteristic peaks occur at 9.0, 13.9, 14.8, 21.5, 24.7, and 29.8±0.2°2θ. Additional peaks occur at 17.0°, 20.6°, 20.8°, 22.4°, 25.8°, 27.7°,28.4°, 28.7°, 29.1°, 30.8°, 31.9°, 32.3°, and 32.9° 2θ±0.2° 2θ. Thehydration level of Zoledronic acid form XII is indicated by a LOD ofabout 6-10%, preferably 6% (monohydrate) on heating from about 25-220°C.

Zoledronic acid Form XII can be prepared by treating Zoledronic acidform XVIII in water at reflux temperature, the diluent/solid ratio being10-30 volumes, preferably 24-26 volumes, and cooling the solution toroom temperature or less.

Zoledronic Form XII can be also be prepared by stirring Form I in aceticacid.

Zoledronic Acid Form XV

In a fourth aspect, the invention provides a novel crystalline solidform of Zoledronic acid denominated Form XV. Zoledronic acid Form XV canbe identified by its PXRD pattern, a representative example of which isprovided in FIG. 5. Particular characteristic peaks occur at 10.1°,17.3°, 19.3°, and 23.2° 2θ±0.2° 2θ. Additional peaks occur at 14.5°,16.7°, 18.1°, 24.5°, 25.1°, 25.7°, 28.5°, 29.1°, 29.6°, and 30.4°2θ±0.2° 2θ. The TGA of form XV shows a LOD of 1% (anhydrous) within thetemperature range 25-220° C.

Zoledronic acid Form XV can be prepared by treating any form ofZoledronic acid (preferably form I) and sodium hydroxide (1:1 moleratio) in absolute ethanol (10 volumes per grams of ZLD-Ac) at refluxtemperature for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic acid Form XV can also be prepared by treating any form ofZoledronic acid (preferably form I or form XII) and sodium hydroxide(1:1 mole ratio) in methanol (10 volumes per grams of ZLD-Ac) at refluxtemperature for a duration of 5-20 hours, most preferably 10-16 hours.

Zoledronic Acid Form XVIII

In a fifth aspect, the invention provides a novel crystalline solid formof Zoledronic acid denominated Form XVIII. Zoledronic acid Form XVIIIcan be identified by its PXRD pattern, a representative example of whichis provided in FIG. 6. Particular characteristic peaks occur at 10.7°,13.0°, 16.4°, 17.4°, and 28.5° 2θ±0.2° 2θ. Additional peaks occur at13.3°, 18.1°, 19.3°, 21.3°, 23.7°, 25.9°, 31.5°, and 34.5° 2θ±0.2° 2θ.The TGA weight loss curve of Zoledronic acid form XVIII shows a LODbetween 0.3% and about 6%, preferably 6% (monohydrate) within thetemperature range 25-220° C.

Zoledronic acid Form XVIII can be prepared by a reaction of1-Imidazoleacetic acid, Phosphorous acid and Silicon oil. Phosphorousoxychloride is added to the reaction mixture at 80° C. and the reactionmixture is stirred at this temperature for 22 hours. The aqueous phaseis separated after addition of water and heated to reflux temperaturefor a 16 hours. Then absolute ethanol is added and the solution is keptat reflux temperature for 2 hours. Then the solution is cooled graduallyto 25° C. to obtain a precipitate of ZLD-Ac.

Zoledronic acid Form XVIII can be also prepared by treating Zoledronicacid form I in methanol, 1-butanol, MTBE, acetonitrile, methanol/water1:1 or ethanol water 1:1 (10 volumes per grams of ZLD-Ac), at roomtemperature or reflux temperature, for a duration of 5-20 hours, mostpreferably 10-16 hours.

Zoledronic Acid Form XX

In a sixth aspect, the invention provides a novel crystalline solid formof Zoledronic acid denominated Form XX. Zoledronic acid Form XX can beidentified by its PXRD pattern, a representative example of which isprovided in FIG. 7. Particular characteristic peaks occur at 12.2°,19.3°, 20.2°, 21.3°, 25.1°, and 27.2° 2θ±0.2° 2θ. Additional peaks occurat 11.4°, 14.9°, 15.5°, 17.2°, 18.2°, and 30.5° 2θ±0.2° 2θ. The TGAweight loss curve of Zoledronic acid form XX shows a LOD of about 0.5%(anhydrous) within the temperature range 25-220° C.

Zoledronic acid Form XX can be prepared by treating Zoledronic acid formI in ethanol, (preferably absolute), 1-propanol, 2-propanol (IPA),preferably at reflux temperature, the diluent/solid ratio being 15-25volumes, preferably 10 volumes, for a duration of 5-20 hours, mostpreferably 10-16 hours.

Zoledronic Acid Form XXVI

In a seventh aspect, the invention provides a novel crystalline solidform of Zoledronic acid, denominated Form XXVI. Zoledronic acid FormXXVI can be identified by its PXRD pattern, a representative example ofwhich is provided in FIG. 8. Particular characteristic peaks occur at9.8°, 14.5°, 17.1°, 17.6°, and 18.3° 2θ±0.2° 2θ. Additional peaks occurat 18.8°, 19.7°, 21.4°, 25.7°, 26.6°, and 28.1° 2θ±0.2° 2θ. The TGAweight loss curve of Zoledronic acid form XXVI shows typically a LOD ofabout 1.3% (anhydrous) within the temperature range 25-220° C.

Zoledronic acid Form XXVI can be prepared by treating Zoledronic acidform I in 2-butanol, preferably at reflux temperature. The diluent/solidratio being 15-25 volumes, preferably 10 volumes, for a duration of 5-20hours, most preferably 10-16 hours.

Crystal Forms of Zoledronic Acid Sodium Salt

In addition, it was also discovered that Zoledronic acid sodium salt ina crystalline form could be obtained. Use of salts in drugs is verydiffused, due to the improved physico-chemical properties over the freeacid or free base, mainly solubility or crystallinity properties. Thecrystalline state of a drug, in general, has an advantage over theamorphous state in that the physical (and chemical) properties are fullycontrolled and reproduced, and the capability of a material tocrystallize in a solid form makes this material feasible forpharmaceutical uses. Hence, the novel crystalline Zoledronate sodiumsalt may have improved solubility. In addition, it was found that thesodium salts obtained have a purity of at least 99.9% area by HPLC.

Surprisingly, it was also discovered that Zoledronate sodium salt cancrystallize in different crystal forms.

The level of sodium is measured by methods known in the art, like atomicabsorption.

Zoledronate sodium can be found in a monosodium salt, disodium salt,trisodium salt, each of them in various hydration states. TheZoledronate monosodium salt has a sodium content in the range of 6-8%w/w. Zoledronate disodium has a sodium content in the range of 11-13%w/w, and Zoledronate trisodium has a sodium content in the range of17-19% w/w.

The level of water in Zoledronate sodium is estimated by TGA(thermogravimetric analysis) weight loss. The Zoledronate sodium saltcan be anhydrous (weight loss up to 2%), a hemihydrate (weight loss 3-4%w/w), a monohydrate (weight loss 5-6%), a sesquihydrate (weight loss7-8%), a dihydrate (weight loss 9-12% w/w), a trihydrate (13-16% weightloss), or a tetrahydrate (weight loss 17-19% w/w).

In general, sodium salts of Zoledronic acid may be prepared by treatingZoledronic acid with a base, preferably NaOH, in organic solvents, likelower alcohols or DMF, and water in different proportions relative tothe organic solvent. The reaction is preferably carried out at refluxtemperature. In these procedures a solution of a base in a mixture ofalcohol/water is added to a suspension of Zoledronic acid in anequivalent mixture of alcohol/water at reflux temperature. The volumeratio of diluent/Zoledronic acid is 6-14, preferably 10 volumes. Thereaction mixture is stirred at reflux temperature for 10-20 hours,preferably 14-16 hours. The reaction mixture can be cooled to roomtemperature or less, and filtered, or filtered at higher temperatures.

Alternatively, sodium salts of Zoledronic acid may be prepared bydissolving Zoledronic acid in water, adding a base, preferably NaOH, andprecipitating it by cooling, optionally with the aid of an organicsolvent such as isopropyl alcohol.

Alternatively, sodium salts of Zoledronic acid may be recrystallized bytreating the sodium salt of Zoledronic acid in water (20-30 volumes,preferably 25 volumes) at reflux temperature and then cooling thesolution to less than room temperature to obtain a precipitate ofZLD-Na.

Zoledronate Monosodium Crystal Forms

Zoledronate monosodium can be found in crystal Form VIII, characterizedby typical PXRD peaks at 8.2°, 15.5°, 18.6°, 23.6°, and 26.8° 2θ±0.2°2θ, and additional peaks at 11.8°, 17.6°, 20.1°, 24.7°, 25.0°, 28.4°,31.7°, 32.8° 2θ±0.2° 2θ. The TGA of form VIII shows a weight loss of15-16% (trihydrate) within the temperature range 25-220° C.

Zoledronate monosodium can be found in crystal form XVI, characterizedby typical XRD peaks at 7.3°, 8.8°, 14.7°, 21.8°, and 29.6° 2θ±0.2° 2θ,and additional peaks at 13.8°, 16.8°, 20.4°, 21.4°, 24.4°, 25.6°, 27.5°,28.2°, and 31.7° 2θ±0.2° 2θ. The TGA curve of form XVI shows a weightloss of 9-10% (dihydrate) within the temperature range 25-220° C.

Zoledronate monosodium can be found in crystal form XVII, characterizedby typical XRD peaks at 8.2°, 9.0°, 14.5°, 21.4°, 24.5°, 29.2° 2θ±0.2°2θ, and additional peaks at 13.9°, 15.5°, 16.8°, 18.6°, 22.3°, 23.6°,26.7°, 27.7°, and 32.3° 2θ±0.2° 2θ. The TGA of form XVII shows a weightloss of about 10% (dihydrate) within the temperature range 25-220° C.

Zoledronate monosodium form VIII may be prepared by dissolvingZoledronic acid in water, adding NaOH in pellets or in aqueous solution(40%). IPA may be added to improve the yield of crystallization. Thissolution is cooled to get form VIII.

Zoledronate monosodium form VIII may be also obtained by treatingZoledronic acid, preferably form I, and sodium hydroxide (ratio ofacid/base 1:1) in water/ethanol 80%:20% v/v, water/methanol 80%:20% v/v,water/isopropanol 80%:20% v/v or 60%:40% v/v.

Zoledronate monosodium form XVI may be obtained by treating Zoledronicacid, preferably form I, and sodium hydroxide (ratio of acid/base 1:1)in water/ethanol 50%:50% v/v or water/isopropanol 50%:50% v/v, orwater/methanol 50%:50% v/v.

Zoledronate monosodium form XVII may be obtained by dissolvingZoledronic acid in water, adding NaOH in aqueous solution (29%)drop-wise (ratio of acid/base 1:0.7)

Zoledronate Disodium Crystal Forms

Zoledronate disodium can be found in form V, characterized by typicalpeaks at 11.3°, 14.8°, 15.5°, 17.4°, 19.9° 2θ±0.2° 2θ, and additionalpeaks at 18.0°, 18.9°, 19.7°, 22.7°, 25.0°, 26.7°, 30.9°, and 34.5°2θ±0.2° 2θ. The TGA curve of form V shows a weight loss of about 10-11%(dihydrate) within the temperature range 25° to 220° C.

Zoledronate disodium form V may be prepared by treating Zoledronic acid,preferably form XII, and sodium hydroxide (ratio of acid/base 1:1.1) inwater/ethanol ratios between 20%-50% v/v water in ethanol,water/methanol ratios between 40%-50% v/v water in methanol, water/IPAratios between 40%-50% v/v water in IPA.

Zoledronate disodium form V may also be prepared by treating Zoledronicacid, preferably form I, and sodium hydroxide (ratio of acid/base 1:2)in water/ethanol ratios between 20%-50% v/v water in ethanol,water/methanol 50%:50% v/v water in methanol, water/isopropanol ratiosbetween 20%-50% v/v water in IPA.

Zoledronate disodium form V may also be prepared by treating Zoledronicacid, preferably form XII, and sodium hydroxide (ratio of acid/base1:1.1) in water/ethanol ratios between 20%-50% v/v water in ethanol,water/methanol ratios between 40%-50% v/v water in methanol, water/IPAratios between 40%-50% v/v water in IPA.

Zoledronate disodium can be found in form VI, characterized by typicalpeaks at 7.2°, 13.3°, 13.7°, 14.5°, 21.7° 2θ±0.2° 2θ, and additionalpeaks at 8.2°, 16.6°, 16.9°, 17.3°, 25.9°, 26.6°, 30.7°, 31.9°, 32.9°2θ±0.2° 2θ. The TGA curve of form VI shows a weight loss of 13-16%(trihydrate) within the temperature range 25-220° C.

Zoledronate disodium form VI may be prepared by treating Zoledronicacid, preferably form XII, and sodium hydroxide (ratio of acid/base1:1.1) in water/ethanol or water/methanol 60% v/v water in ethanol ormethanol, or water/isopropanol 80% v/v water in IPA.

Zoledronate disodium form VI may also be obtained also byrecrystallizing Zoledronate disodium, preferably form XIX, in water.

Zoledronate disodium can be found in form VII, characterized by typicalpeaks at 6.2°, 11.6°, 12.6°, and 13.7° 2θ±0.2° 2θ, and additional peaksat 22.0°, 23.2°, 26.4°, 27.1°, 28.6°, 28.8°, 34.2° 2θ±0.2° 2θ. The TGAcurve of form VII shows a weight loss of 17-19% within the temperaturerange 25-220° C. (tetrahydrate). Less crystalline form VII is found withwater content of 7-10% within the temperature range 25-220° C.

Zoledronate sodium form VII may be obtained by dissolving Zoledronicacid in water, adding a base, preferably NaOH (aqueous solution orpearls) until the pH of 5.5-7.5, preferably 5.7-7.0. The solution iscooled and optionally an organic solvent (preferably isopropanol) isadded. Optionally the solution may be concentrated to obtain the solidmaterial. The mixture may be further stirred for a period of 1-5 hours,preferably 2 hours.

Zoledronate disodium form VII may be also prepared by treatingZoledronic acid, preferably form XII, and sodium hydroxide (ratio ofacid/base 1:1.1) in water/ethanol or water/methanol or water/isopropanol80%:20% v/v of water in the alcohol.

Zoledronate disodium form VII may be also prepared by treatingZoledronic acid, preferably form XII, and sodium hydroxide (ratio ofacid/base 1:1.1) in water/isopropanol 60%:40% v/v water in IPA.

Zoledronate disodium form VII may be also prepared by treatingZoledronic acid, preferably form I, and sodium hydroxide (ratio ofacid/base 1:2) in water/ethanol 80%:20% v/v water in ethanol.

Zoledronate disodium can be found in form X, characterized by typicalpeaks at 6.7°, 14.4°, 18.2°, 20.4°, and 20.7° 2θ±0.2° 2θ, and additionalpeaks at 8.8°, 13.7°, 17.0°, 19.8°, 21.3°, 24.4°, 27.5°, 27.9°, 30.9°,and 33.4° 2θ±0.2° 2θ. The TGA curve of form X shows a weight loss ofabout 3% (hemihydrate) within the temperature range 25° to 220° C.

Zoledronate disodium form X may be obtained by treating Zoledronic acid,preferably form XII, and sodium hydroxide (ratio of acid/base 1:1.1) inwater/isopropanol 20%:80% v/v water in IPA.

Zoledronate disodium can be found in form XIII, characterized by typicalpeaks at 6.5°, 13.0°, 16.1°, 17.2°, and 30.7° 2θ±0.2° 2θ, and additionalpeaks at 10.2°, 19.0°, 20.0°, 20.6°, 22.3°, 27.4°, 28.6°, 28.9°, 34.8°2θ±0.2° 2θ. The TGA curve of form XIII shows a weight loss of about 3%(hemihydrate) within the temperature range 25-220° C.

Zoledronate disodium form XIII may be obtained by treating Zoledronicacid, preferably form I, and sodium hydroxide (ratio of acid/base 1:2)in water/ethanol 5%:95% v/v water in ethanol.

Zoledronate disodium can be found in form XIV, characterized by typicalpeaks at 6.6°, 19.9°, 28.5°, 34.8° 2θ±0.2° 2θ, and additional peaks at13.0°, 15.1°, 17.1°, 20.5°, 27.7°, 29.6°, 30.7°, 33.5° 2θ±0.2° 2θ. TheTGA curve of form XIV shows a weight loss of 1-2% (anhydrous) within thetemperature range 25-220° C.

Zoledronate disodium form XIV may be obtained by treating Zoledronicacid, preferably form I, and sodium hydroxide (ratio of acid/base 1:2)in water/methanol 20%:80% v/v water in methanol.

Zoledronate disodium form XIV may be also obtained by treatingZoledronic acid, preferably form XII, and sodium hydroxide (ratio ofacid/base 1:1) in water/DMF 20%:80% v/v water in DMF.

Zoledronate disodium can be found in form XIX, characterized by typicalX-Ray peaks at 11.6°, 12.5°, 13.7°, 22.0°, 23.1 ° 2θ±0.2° 2θ, andadditional peaks at 6.2°, 14.3°, 15.3°, 16.0°, 18.5°, 24.3°, and 28.6°2θ±0.2° 2θ. The TGA curve of form XIX shows a weight loss of about 22%(pentahydrate) within the temperature range 25° to 220° C.

Zoledronate disodium form XIX may be obtained by treating Zoledronatedisodium, preferably form VII, in water and precipitating the material,preferably by cooling.

Zoledronate disodium form XIX may be also obtained by dissolvingZoledronic acid in water, adding a base, preferably NaOH (aqueoussolution or pearls) (ratio of acid/base 1:2), in reflux.

Zoledronate disodium can be found in form XXV, characterized by typicalpeaks at 7.4°, 13.7°, 17.6°, and 21.9° 2θ±0.2° 2θ, and additional peaksat 6.3°, 9.5°, 12.6°, 14.6°, 26.2°, 27.1°, and 28.6° 2θ±0.2° 2θ. The TGAcurve of form XXV shows a weight loss of 7 to 8% (sesquihydrate) withinthe temperature range of 25° to 220° C.

Zoledronate disodium form XXV may be obtained by treating Zoledronicacid, preferably form I, and sodium hydroxide (ratio of acid/base 1:2)in water/methanol 80%:20% v/v water in methanol.

Zoledronate disodium can be found in form XXVII, characterized bytypical peaks at 6.4°, 8.2°, 16.0°, 17.4°, 19.0°, 28.8° 2θ±0.2° 2θ, andadditional peaks at 7.7°, 10.2°, 17.2°, 18.1°, 21.6°, 25.7°, 25.9°2θ±0.2° 2θ. The TGA curve of form XXVII shows a weight loss of about5-6% (monohydrate) within the temperature range 25-220° C.

Zoledronate disodium form XXVII may be prepared by treating Zoledronicacid, preferably form I, and sodium hydroxide (ratio of acid/base 1:2)in water/methanol 5%:95% v/v water in methanol and by treatingZoledronic acid, preferably form XII, and sodium hydroxide (ratio ofacid/base 1:1) in water/methanol 20%:80% v/v water in methanol.

Zoledronate Trisodium Crystal Forms

Zoledronate trisodium can be found in form IX, characterized by typicalpeaks at 8.3°, 10.9°, 15.0°, 16.6°, and 22.8° 2θ±0.2° 2θ, and additionalpeaks at 13.1°, 20.2°, 20.6°, 20.9°, 25.0°, 27.8°, and 29.0° 2θ±0.2° 2θ.The TGA curve of form IX shows a weight loss of about 13-14%(trihydrate) within the temperature range 25-220° C.

Zoledronate trisodium form IX may be prepared by treating Zoledronicacid, preferably form XII, and sodium hydroxide (ratio of acid/base1:2.1) in water/ethanol or water/methanol or water/isopropanol in ratiosbetween 20%-80% v/v of water in the alcohol.

Zoledronate trisodium can be found in form XI, characterized by typicalpeaks at 6.2°, 7.9°, 8.8°, 10.6°, 12.2° 2θ±0.2° 2θ, and additional peaksat 15.0°, 15.4°, 17.5°, 18.8°, 19.6°, 20.5°, 22.3°, 23.7°, 25.7°, 29.6°,and 31.7° 2θ±0.2° 2θ. The TGA curve of form XI shows a weight loss ofabout 9% (dihydrate) within the temperature range 25-220° C.

Zoledronate disodium form XI may be prepared by treating Zoledronicacid, preferably form XII, and sodium hydroxide (ratio of acid/base1:2.1) in water/ethanol or water/methanol 5%:95% v/v of water in ethanolor methanol.

Zoledronate Sodium Amorphous

Zoledronate sodium amorphous is prepared by treating Zoledronic acid andsodium hydroxide (ratio of acid/base 1:0.1 or 1:2.1 or 1:3.1) in waterat room temperature, and precipitating the material by concentrating thesolution by any means known in the art like evaporation of the solvent.Evaporation may be done using a vacuum.

EXAMPLES Crystal Forms of Zoledronic Acid (ZLD-Ac)

Preparation of ZLD-Ac Crystal Form I

General procedure for the preparation of ZLD-Ac crystal form I startingfrom 1-Imidazoleacetic acid (IAA), Phosphorous acid (H₃PO₃) andPhosphorous oxychloride (POCl₃) (Examples 1-9, see Table 1):

A cylindrical reactor equipped with a mechanical stirrer, a thermometer,a reflux condenser and a dropping funnel, is loaded with1-Imidazoleacetic acid (IAA), Phosphorous acid and a diluent(Toluene/Chlorobenzene/PEG-400/Silicon oil). The obtained suspension isheated to 75° C.-80° C. and Phosphorous oxychloride is added drop-wise.The reaction mixture is then heated to 75° C.-100° C. for 1-34 hours.Then water is added at 80° C.-100° C. The mixture is stirred vigorouslyfor about 15 minutes. [In some cases, when Silicon oil is used as adiluent, there is a need to add Toluene in order to improve theseparation between the oily phase and the aqueous phase]. Then thephases are separated. The aqueous phase is put in a clean reactor andheated to 95° C.-100° C. for 13.5-19 hours. Then it is cooled to 5° C.and absolute Ethanol is added to obtain a precipitate after stirring at5° C. for 2.5-4 hours [In some cases a precipitate of Zoledronic acid isobtained without adding absolute Ethanol as an anti-solvent]. The whiteproduct is then filtered, washed with absolute Ethanol and dried in avacuum oven at 50° C. for 17-24 hours to obtain Zoledronic acid crystalform I (LOD by TGA=6.3%-9.3%).

TABLE 1 Preparation of ZLD-Ac crystal form I starting from IAA, H₃PO₃and POCl₃ Ratio of Amount Addition Amount of abs. Raw reactants Diluent/of water of Toluene EtOH/Acetone material (equivalents) volumes for theto improve Time of for the LOD Yield (grams IAA/H₃PO₃/ per grams Temp.of Time of hydrolysis phases hydrolysis precipitation by (grams ofExample of IAA) POCl₃ of IAA reaction reaction step separation step ofZLD-Ac TGA ZLD-Ac) 1 IAA.HCl 1/3.6/4.5 Silicon oil/ 80° C. 24 hrs 45 ml50 ml 19 hrs 90 ml 9.1% 79% (5.4 g) 6.5 vol. (EtOH) (7.8 g) 2 IAA.HCl1/3.7/3.7 Chloro- 100° C.  1 hr 50 ml — 15.5 hrs  50 ml — — (4.9 g)benzene/ (EtOH) (8.2 g) 8.8 vol. 3 IAA.HCl 1/3/3 PEG-400/ 75° C.  2 hrs27 ml 27 ml 13.5 hrs  100 ml  — — (4.9 g) 5.5 vol. (Acetone) (1.1 g) 4IAA.HCl 1/3/3.75 Silicon oil/ 80° C. 22 hrs 54 ml 54 ml 19 hrs 54 ml6.8% 76% (4.9 g) 5.5 vol. (EtOH) (6.7 g) 5 IAA.HCl 1/3.7/3.7 Toluene/100° C.   3 hrs 44 ml — 16 hrs 200 ml  9.3% 69% (4.9 g) 8.8 vol. (EtOH)(6.2 g) 6 IAA.HCl 1/2/3 Silicon oil/ 80° C. 23 hrs 33 ml — 16 hrs 200ml  7.9% 38% (5.9 g) 5.5 vol. (EtOH) (4.0 g) 7 IAA.HCl 1/4/4 Siliconoil/ 80° C. 11 hrs 33 ml 33 ml 16 hrs 33 ml 9.3% 74% (6.0 g) 5.5 vol.(EtOH) (8.2 g) 8 IAA 1/3/3.75 Silicon oil/ 80° C. 17 hrs 72 ml — 16 hrs— 7.7% 72% MS-427 (12.0 g) 6.0 vol. (20.0 g)  9 IAA 1/3/3.75 Siliconoil/ 80° C. 34 hrs 490 ml  490 ml  16 hrs 490 ml  6.3% 59% (70 g) 7.0vol. (EtOH) (95.1 g)  (addition of Purity by EtOH at HPLC 98.3%* refluxtemp.) ZLD HPLC method: Column: Phenomenex Phenyl-Hexyl 5 μm, 250 × 4.6mm Mobile phase: 40 mM Octansulfonic acid sodium salt in 1% HClO₄, 0.2%H₃PO₄:Methanol (85:15)Detection: 220 nmStability was measured versus the presence of Form II.The stability data for example 4 in the table above is:

TGA analysis Example Results No. Time Interval 25° C., 40° C., 4(months) 60% RH 75% RH 55° C. 2-8° C. ZLD-Ac 0  I I I I I 1 M I I 2 M II 3 M I I 6 M I I I I 9 M 12 M  ZLD-Ac 0  1 M 2 M 6.3 6.3 3 M 6.2 6.2 6M 6.5 6.5 6.5 6.4 9 M 12 M 

Example 10

Sodium hydroxide (pearls, 91.1 g) was added to a suspension ofZoledronic acid crystal form XII (200.0 g) in water (2000 ml) at roomtemperature (pH=14) to obtain a clear solution. Then the pH of thesolution was adjusted to pH 1 by addition of 32% aqueous HCl (300 ml).The solution was then cooled gradually to 5° C. and the whiteprecipitate was filtered, washed with cold water (2×150 ml) and dried ina vacuum oven at 50° C. for 24 hours to obtain 161.7 g (84%) ofZoledronic acid crystal form I (LOD by TGA=6.7%). Purity by HPLC 99.9%.

Preparation of ZLD-Ac Crystal Form II

Example 11

A 250 ml three-necked flask equipped with a mechanical stirrer, a refluxcondenser and a dropping funnel, was loaded with 1-Imidazoleacetic acidhydrochloride (4.9 g, 0.03 mole), phosphorous acid (4.9 g, 0.06 mole)and Silicon oil (Merck) (27 ml). The suspension was heated to 75° C. andphosphorous oxychloride (10.5 ml, 0.11 mole) was added drop-wise during30 minutes. The reaction mixture was then heated to 80° C. for 27 hours.Then water (27 ml) and toluene (30 ml) were added at 80° C. The mixturewas stirred vigorously for about 15 minutes. Then the toluene phase(containing the silicon oil) and the aqueous phase were separated. Theaqueous phase was put in a clean flask and heated to 90° C. for 16hours. Then it was cooled to room temperature and absolute Ethanol (27ml) was added during the cooling process to obtain a white precipitateimmediately. The mixture was stirred at 5° C. for 4 hours. The whiteproduct was then filtered, washed with absolute Ethanol (2×15 ml) anddried in a vacuum oven at 50° C. for 24 hours to obtain 4.9 g (58%) ofZoledronic acid crystal form II (LOD by TGA=5.2%).

Example 12

Zoledronic acid crystal form I (2.0 g) was stirred in Toluene (20 ml) atreflux temperature for 14 hours. Then the suspension was cooled to roomtemperature, filtered, washed with Toluene (1×15 ml) and dried in avacuum oven at 50° C. for 24 hours to obtain 1.6 g of Zoledronic acidcrystal form II.

Preparation of ZLD-Ac Crystal Form XII

Example 13

Zoledronic acid crystal form XVIII (10.0 g) was dissolved in water (260ml) at reflux temperature. The obtained solution was stirred at refluxtemperature for about 20 minutes to obtain a clear solution. Then it wascooled to 75° C. during 2 hours and stirred at this temperature for 1hour. The turbid solution was further cooled to 25° C. during 4.5 hoursand stirred at this temperature for 1 hour. After cooling to 0° C.during 2 hours and stirring at this temperature for 16 hours, the whiteprecipitate was filtered and dried in a vacuum oven at 50° C. for 24hours to obtain 7.8 g of Zoledronic acid crystal form XII.

Example 14

Zoledronic acid crystal form I (2.0 g) was stirred in Acetic acid (20ml) at room temperature for 15.5 hours. Then it was filtered, washedwith Acetic acid (2×5 ml) and dried in a vacuum oven at 50° C. for 24hours to obtain 2.0 g of Zoledronic acid crystal form XII.

Preparation of ZLD-Ac Crystal Form XV

Example 15

A 250 ml flask was loaded with Zoledronic acid form I (4.8 g), Sodiumhydroxide (0.7 g) and absolute Ethanol (10 volumes per grams of ZLD-Ac)(48 ml). The reaction mixture was heated to reflux temperature for 16hours. Then it was cooled to room temperature. Further cooling wasperformed using an ice-bath. The precipitate was then filtered, washedwith absolute Ethanol (2×20 ml) and dried in a vacuum oven at 50° C. for23 hours to give 4.9 g (96%) of Zoledronate monosodium crystal form XVin a mixture with Zoledronic acid crystal form I (LOD by TGA=5.8%).

Example 16

A 250 ml flask was loaded with Zoledronic acid form I (4.8 g), Sodiumhydroxide (0.7 g) and Methanol (10 volumes per grams of ZLD-Ac) (48 ml).The reaction mixture was heated to reflux temperature for 16 hours. Thenit was cooled to room temperature. Further cooling was performed usingan ice-bath. The precipitate was then filtered, washed with Methanol(2×10 ml) and dried in a vacuum oven at 50° C. for 22 hours to give 4.8g (99%) of Zoledronate monosodium crystal form XV (LOD by TGA=0.8%).Purity by HPLC 99.9%.

Example 17

Zoledronic acid crystal form XII (2.0 g) was stirred in Methanol (20 ml)at reflux temperature for 19 hours. Then the suspension was cooled toroom temperature, filtered, washed with Methanol (1×5 ml) and dried in avacuum oven at 50° C. for 24 hours to obtain 1.8 g of a mixture ofZoledronic acid crystal forms XV and XVIII.

Preparation of ZLD-Ac Crystal Form XVIII

Example 18

A 3 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with1-Imidazoleacetic acid (70.0 g, 0.56 mole), Phosphorous acid (136.7 g,1.67 mole) and Silicon oil (M-350) (490 ml). The suspension was heatedto 80° C. and Phosphorous oxychloride (194.4 ml, 2.08 mole) was addeddrop-wise during 4 hours. The reaction mixture was stirred at 80° C. for22 hours. Then water (490 ml) was added slowly at 80° C. The mixture wasstirred vigorously for about 30 minutes. Then the silicon oil phase andthe aqueous phase were separated. The aqueous phase was put in a cleanreactor and heated to 97° C. for 17.5 hours. Then absolute Ethanol (490ml) was added and the solution was stirred at reflux (87° C.) for 2hours. The solution was then cooled to 70° C.-72° C. during about 1 hourand was kept at this temperature for 1 hour. After cooling to 25° C.during 2.5 hours and stirring at this temperature for 1 hour, half ofthe product was filtered, washed with small amount of cold water anddried in a vacuum oven at 50° C. for 20 hours to obtain 50.8 g ofZoledronic acid crystal form XVIII (MS-507-crop I, LOD by TGA=1.9%). Therest of the suspension was cooled to 0° C. during 2 hours and wasstirred at this temperature for about 16 hours. Then the product wasfiltered and dried in a vacuum oven at 50° C. for 24 hours to obtain 26g of Zoledronic acid crystal form XVIII (MS-507-crop II, LOD byTGA=1.0%). The overall yield of the process is 50% purity by HPLC 97.7%.

Example 19

Zoledronic acid crystal form I (2.0 g) was stirred in Methanol (20 ml)at room temperature for 14.5 hours. Then it was filtered, washed withMethanol (2×10 ml) and dried in a vacuum oven at 50° C. for 25 hours toobtain 1.9 g of Zoledronic acid crystal form XVIII.

Example 20

Zoledronic acid crystal form I (2.0 g) was stirred in Methanol (20 ml)at reflux temperature for 16 hours. Then the suspension was cooled toroom temperature and the white solid was filtered, washed with Methanol(2×5 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 1.7g of Zoledronic acid crystal form XVIII.

Example 21

Zoledronic acid crystal form I (2.0 g) was stirred in 1-Butanol (20 ml)at reflux temperature for 15.5 hours. Then the suspension was cooled toroom temperature and the white solid was filtered, washed with 1-Butanol(1×5 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain 1.8g of Zoledronic acid crystal form XVIII.

Example 22

Zoledronic acid crystal form I (2.0 g) was stirred in MTBE (20 ml) atreflux temperature for 15 hours. Then the suspension was cooled to roomtemperature and the white solid was filtered, washed with MTBE (1×10 ml)and dried in a vacuum oven at 50° C. for 25 hours to obtain 1.4 g ofZoledronic acid crystal form XVIII.

Example 23

Zoledronic acid crystal form I (2.0 g) was stirred in Acetonitrile (20ml) at room temperature for 22 hours. Then the suspension was filtered,washed with Acetonitrile (2×5 ml) and dried in a vacuum oven at 50° C.for 23 hours to obtain 2.0 g of Zoledronic acid crystal form XVIII.

Example 24

Zoledronic acid crystal form I (2.0 g) was stirred in a mixture ofMethanol/water (1:1 v/v) (20 ml) at reflux temperature for 18 hours.Then the suspension was cooled to 0° C., filtered and dried in a vacuumoven at 50° C. for 22 hours to obtain 1.8 g of Zoledronic acid crystalform XVIII.

Example 25

Zoledronic acid crystal form I (2.0 g) was stirred in a mixture ofEthanol/water (1:1 v/v) (20 ml) at reflux temperature for 18 hours. Thenthe suspension was cooled to 0° C., filtered and dried in a vacuum ovenat 50° C. for 22 hours to obtain 1.8 g of Zoledronic acid crystal formXVIII.

Preparation of ZLD-Ac Crystal Form XX

Example 26

Zoledronic acid crystal form I (2.0 g) was stirred in absolute Ethanol(20 ml) at reflux temperature for 16 hours. The suspension was thencooled to room temperature and the white solid was filtered, washed withabsolute Ethanol (2×5 ml) and dried in a vacuum oven at 50° C. for 22.5hours to obtain 1.9 g of Zoledronic acid crystal form XX in a mixturewith crystal form I.

Example 27

Zoledronic acid crystal form I (2.0 g) was stirred in 1-Propanol (20 ml)at reflux temperature for 11.5 hours. The suspension was then cooled toroom temperature and the white solid was filtered, washed with1-Propanol (2×5 ml) and dried in a vacuum oven at 50° C. for 24 hours toobtain 1.9 g of Zoledronic acid crystal form XX.

Example 28

Zoledronic acid crystal form I (2.0 g) was stirred in 2-Propanol (IPA)(20 ml) at reflux temperature for 14 hours. The suspension was thencooled to room temperature and the white solid was filtered, washed withIPA (2×5 ml) and dried in a vacuum oven at 50° C. for 24 hours to obtain1.9 g of Zoledronic acid crystal form XX. Purity by HPLC 99.8%.

Preparation of ZLD-Ac Crystal Form XXVI

Example 29

Zoledronic acid crystal form I (2.0 g) was stirred in 2-Butanol (20 ml)at reflux temperature for about 15 hours. The suspension was then cooledto room temperature and the white solid was filtered, washed with2-Butanol (2×5 ml) and dried in a vacuum oven at 50° C. for 24 hours toobtain 1.9 g of Zoledronic acid crystal form XXVI.

Crystal Forms of Zoledronate Monosodium (ZLD-Na)

Preparation of ZLD-Na Crystal Form VIII

Example 30

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometerand a reflux condenser was loaded with Zoledronic acid form I (10.0 g)and water (247 ml). The suspension was heated to 94° C. to obtain aclear solution. Sodium hydroxide (pearls, 1.42 g) was added. A pH testof the sodium salt showed pH=4.54. The solution was cooled to 60° C. andIPA (10.5 ml) was added. The reaction mixture was cooled to roomtemperature during 2 hours and was stirred at this temperature for about64 hours. After cooling to 5° C. and stirring at this temperature for 1hour, the white precipitate was filtered, washed with cold water (1×10ml) and dried in a vacuum oven at 50° C. for 23.5 hours to obtain 7.0 gof Zoledronate monosodium crystal form VIII (pH=4.32). Purity by HPLC100.0%.

Example 31

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with Zoledronic acidform I (10.0 g) and water (247 ml). The suspension was heated to 94° C.to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide(3.45 g) was added drop-wise. The solution was then cooled to 4° C.during 2 hours and was stirred at this temperature for about 64 hours toobtain a massive precipitate. The white precipitate was filtered, washedwith cold water (1×10 ml) and dried in a vacuum oven at 50° C. for 26hours to obtain 7.6 g (64%) of Zoledronate monosodium crystal form VIII(LOD by TGA=15.1%).

Example 32→

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with Zoledronic acidform I (10.0 g) and water (247 ml). The suspension was heated to 94° C.to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide(3.45 g) was added drop-wise. The solution was then cooled to roomtemperature and stirred at this temperature for 16 hours. After coolingto 3° C. and stirring at this temperature for 1.5 hour, the whiteprecipitate was filtered, washed with Methanol (2×15 ml) and dried in avacuum oven at 50° C. for 25 hours to obtain 5.8 g (49%) of Zoledronatemonosodium crystal form VIII (LOD by TGA=15.1%). The obtained Form VIII(2 g) was recrystallized form water (34 ml) to give 1.4 g (72%) ofZoledronic acid crystal form VIII (LOD by TGA=11.3%). Purity by HPLC100.0%.

Remark:

Regarding the next examples: the composition of the reflux media isexpressed on a volume per volume basis (abbreviated v/v). The amount ofwater that should be added to the reflux media is calculated accordingto the following formula:(10 volumes of alcohol per grams of ZLD-Ac×100)/X % of alcohol=Y when Yis the total amount of alcohol and water together→Y×(100−X)% ofwater/100=Zwhen Z is the volume of water that should be added].

Example 33

A solution of sodium hydroxide (0.7 g) in a mixture of water (80%v/v)/Ethanol (20% v/v, 10 volumes per grams of ZLD-Ac) (36 ml) was addeddrop-wise to a suspension of Zoledronic acid form I (4.8 g) in a mixtureof water (80% v/v)/Ethanol (20% v/v, 10 volumes per grams of ZLD-Ac)(202 ml) at reflux temperature. The reaction mixture was heated atreflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with absoluteEthanol (2×20 ml) and dried in a vacuum oven at 50° C. for 22 hours togive 4.7 g (83%) of Zoledronate monosodium crystal form VIII (LOD byTGA=15.5%). Purity by HPLC 99.9%.

Example 34

A solution of sodium hydroxide (0.7 g) in a mixture of water (80%v/v)/Methanol (20% v/v, 10 volumes per grams of ZLD-Ac fprm I) (36 ml)was added drop-wise to a suspension of Zoledronic acid (4.8 g) in amixture of water (80% v/v)/Methanol (20% v/v, 10 volumes per grams ofZLD-Ac form I) (202 ml) at reflux temperature. The reaction mixture washeated at reflux temperature for additional 16 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed withMethanol (1×20 ml) and dried in a vacuum oven at 50° C. for 22 hours togive 4.7 g (81%) of Zoledronate monosodium crystal form VIII (LOD byTGA=16.03%). Purity by HPLC 99.9%.

Example 35

A solution of sodium hydroxide (0.7 g) in a mixture of water (80%v/v)/IPA (20% v/v, 10 volumes per grams of ZLD-Ac form I) (38 ml) wasadded drop-wise to a suspension of Zoledronic acid (5.0 g) in a mixtureof water (80% v/v)/IPA (20% v/v, 10 volumes per grams of ZLD-Ac form I)(212 ml) at reflux temperature. The reaction mixture was heated atreflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with IPA (2×20 ml)and dried in a vacuum oven at 50° C. for 24 hours to give 4.7 g (79%) ofZoledronate monosodium crystal form VIII (LOD by TGA=15.40%). Purity byHPLC 99.95%.

Example 36

A solution of sodium hydroxide (0.7 g) in a mixture of water (60%v/v)/IPA (40% v/v, 10 volumes per grams of ZLD-Ac form I) (19 ml) wasadded drop-wise to a suspension of Zoledronic acid (5.0 g) in a mixtureof water (60% v/v)/IPA (40% v/v, 10 volumes per grams of ZLD-Ac form I)(106 ml) at reflux temperature. The reaction mixture was heated atreflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with IPA (1×20 ml)and dried in a vacuum oven at 50° C. for 27 hours to give 0.6 g (10%) ofZoledronate monosodium crystal form VIII (LOD by TGA=15.0%).

Preparation of ZLD-Na Crystal Form XVI

Example 37

A solution of sodium hydroxide (0.7 g) in a mixture of water (50%v/v)/Ethanol (50% v/v, 10 volumes per grams of ZLD-Ac form I) (14 ml)was added drop-wise to a suspension of Zoledronic acid (4.8 g) in amixture of water (50% v/v)/Ethanol (50% v/v, 10 volumes per grams ofZLD-Ac form I) (81 ml) at reflux temperature. The reaction mixture washeated at reflux temperature for additional 16 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed withabsolute Ethanol (2×20 ml) and dried in a vacuum oven at 50° C. for 18hours to give 5.2 g (98%) of Zoledronate monosodium crystal form XVI(LOD by TGA=9.9%). Purity by HPLC 99.95%.

Example 38

A solution of sodium hydroxide (0.7 g) in a mixture of water (50%v/v)/IPA (50% v/v, 10 volumes per grams of ZLD-Ac form I) (15 ml) wasadded drop-wise to a suspension of Zoledronic acid (5.0 g) in a mixtureof water (50% v/v)/IPA (50% v/v, 10 volumes per grams of ZLD-Ac form I)(85 ml) at reflux temperature. The reaction mixture was heated at refluxtemperature for additional 16 hours. Then the reaction mixture wascooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with IPA (2×20 ml)and dried in a vacuum oven at 50° C. for 24 hours to give 5.2 g (94%) ofZoledronate monosodium crystal form XVI (LOD by TGA=9.8%). Purity byHPLC 99.9%.

Example 39

A solution of sodium hydroxide (0.7 g) in a mixture of water (50%v/v)/Methanol (50% v/v, 10 volumes per grams of ZLD-Ac form I) (14 ml)was added drop-wise to a suspension of Zoledronic acid form I (4.8 g) ina mixture of water (50% v/v)/Ethanol (50% v/v, 10 volumes per grams ofZLD-Ac form I) (81 ml) at reflux temperature. The reaction mixture washeated at reflux temperature for additional 16 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed withMethanol (1×25 ml) and dried in a vacuum oven at 50° C. for 25.5 hoursto give 4.8 g (89%) of Zoledronate monosodium crystal form XVI (LOD byTGA=11.1%). Purity by HPLC 99.9%.

Preparation of ZLD-Na Crystal Form XVII

Example 40

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with Zoledronic acidform I (10.0 g) and water (247 ml). The suspension was heated to 94° C.to obtain a clear solution. A 29% aqueous solution of Sodium hydroxide(3.45 g) was added drop-wise. The solution was then cooled to roomtemperature and stirred at this temperature for 16 hours. After coolingto 3° C. the product was isolated by filtration. Further cooling of themother-liquid led to the formation of a white precipitate. Theprecipitate was filtered and dried in a vacuum oven at 50° C. for 24hours to obtain 0.6 g of Zoledronate monosodium crystal form XVII (LODby TGA=10.3%).

Crystal Forms of Zoledronate Disodium (ZLD-Na₂)

Preparation of ZLD-Na₂ Crystal Form V

Example 41

A solution of sodium hydroxide (0.7 g) in a mixture of water (X %v/v)/Ethanol (Y % v/v, 10 volumes per grams of ZLD-Ac form XII) (10-15ml) was added drop-wise to a suspension of Zoledronic acid form XII(4.98 g) in a mixture of water (X % v/v)/Ethanol (Y % v/v, 10 volumesper grams of ZLD-Ac) (53-85 ml) at reflux temperature. The reactionmixture was heated at reflux temperature for additional 16 hours. Thenthe reaction mixture was cooled to room temperature. Further cooling wasperformed using an ice-bath. The precipitate was then filtered, washedand dried in a vacuum oven at 50° C. for 24 hours to give Zoledronatedisodium crystal form V.

Total volume Sample X % Y % of solution LOD by No. H₂O EtOH (H₂O/EtOH)Yield (g/%) TGA 1 20% 80% 63 ml 4.9 g/89% 10.3% (13 ml) (50 ml) 2 40%60% 83 ml 5.0 g/90% 10.3% (33 ml) (50 ml) 3 50% 50% 100 ml  5.1 g/91%10.7% (50 ml) (50 ml)

Example 42

A solution of sodium hydroxide (0.7 g) in a mixture of water (X %v/v)/Methanol (Y % v/v, 10 volumes per grams of ZLD-Ac form XII) (13-15ml) was added drop-wise to a suspension of Zoledronic acid form XII(4.98 g) in a mixture of water (X % v/v)/Methanol (Y % v/v, 10 volumesper grams of ZLD-Ac) (70-85 ml) at reflux temperature. The reactionmixture was heated at reflux temperature for additional 16 hours. Thenthe reaction mixture was cooled to room temperature. Further cooling wasperformed using an ice-bath. The precipitate was then filtered, washedand dried in a vacuum oven at 50° C. for 24 hours to give Zoledronatedisodium crystal form V.

Total volume Sample X % Y % of solution LOD by No. H₂O MeOH (H₂O/MeOH)Yield (g/%) TGA 1 40% 60% 83 ml 4.7 g/85% 10.0% (33 ml) (50 ml) 2 50%50% 100 ml  4.9 g/88% 10.8% (50 ml) (50 ml)

Example 43

A solution of sodium hydroxide (0.7 g) in a mixture of water (X %v/v)/IPA (Y % v/v, 10 volumes per grams of ZLD-Ac form XII) (13-15 ml)was added drop-wise to a suspension of Zoledronic acid (4.98 g) in amixture of water (X % v/v)/IPA (Y % v/v, 10 volumes per grams of ZLD-Acform XII) (70-85 ml) at reflux temperature. The reaction mixture washeated at reflux temperature for additional 16 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed and driedin a vacuum oven at 50° C. for 24 hours to give Zoledronate disodiumcrystal form V.

Total volume Sample X % Y % of solution LOD by No. H₂O IPA (H₂O/IPA)Yield (g/%) TGA 1 40% 60% 83 ml 4.7 g — (33 ml) (50 ml) 2 50% 50% 100ml  4.8 g/85% 11.2% (50 ml) (50 ml)

Example 44

A solution of sodium hydroxide (1.4 g) in a mixture of water (X %v/v)/Ethanol (Y % v/v, 10 volumes per grams of ZLD-Ac form I) (10-15 ml)was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) ina mixture of water (X % v/v)/Ethanol (Y % v/v, 10 volumes per grams ofZLD-Ac) (53-85 ml) at reflux temperature. The reaction mixture washeated at reflux temperature for additional 16 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed and driedin a vacuum oven at 50° C. for 24 hours to give Zoledronate disodiumcrystal form V. Purity by HPLC 99.9%.

Total volume Sample X % Y % of solution LOD by No. H₂O EtOH (H₂O/EtOH)Yield (g/%) TGA 1 20% 80% 63 ml 6.0 g/96% 9.7% (13 ml) (50 ml) 2 50% 50%100 ml  6.0 g/94% 10.9%  (50 ml) (50 ml)

Example 45

A solution of sodium hydroxide (1.4 g) in a mixture of water (X %v/v)/Methanol (Y % v/v, 10 volumes per grams of ZLD-Ac form I) (15 ml)was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) ina mixture of water (X % v/v)/Methanol (Y % v/v, 10 volumes per grams ofZLD-Ac) (85 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed and dried in avacuum oven at 50° C. for 24 hours to give Zoledronate disodium crystalform V. Purity by HPLC 99.95%.

Total volume Sample X % Y % of solution LOD by No. H₂O MeOH (H₂O/MeOH)Yield (g/%) TGA 1 50% 50% 100 ml 6.0 g/94% 11.1% (50 ml) (50 ml)

Example 46

A solution of sodium hydroxide (1.4 g) in a mixture of water (X %v/v)/IPA (Y % v/v, 10 volumes per grams of ZLD-Ac form I) (10-15 ml) wasadded drop-wise to a suspension of Zoledronic acid (5.0 g) in a mixtureof water (X % v/v)/IPA (Y % v/v, 10 volumes per grams of ZLD-Ac) (53-85ml) at reflux temperature. The reaction mixture was heated at refluxtemperature for additional 16 hours. Then the reaction mixture wascooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed and dried in avacuum oven at 50° C. for 24 hours to give Zoledronate disodium crystalform V. Purity by HPLC 99.95%.

Total volume Sample X % of solution LOD by No. H₂O Y % IPA (H₂O/IPA)Yield (g/%) TGA 1 20% 80% 63 ml 5.7 g/91% 10.3% (13 ml) (50 ml) 2 50%50% 100 ml  5.7 g/90% 10.6% (50 ml) (50 ml)Preparation of ZLD-Na₂ Crystal Form VI

Example 47

A solution of sodium hydroxide (0.7 g) in a mixture of water (60%v/v)/Ethanol or Methanol (40% v/v, 10 volumes per grams of ZLD-Ac formXII) (19 ml) was added drop-wise to a suspension of Zoledronic acid formXII (4.98 g) in a mixture of water (60% v/v)/Ethanol or Methanol (40%v/v, 10 volumes per grams of ZLD-Ac) (106 ml) at reflux temperature. Thereaction mixture was heated at reflux temperature for additional 16hours. Then the reaction mixture was cooled to room temperature. Furthercooling was performed using an ice-bath. The precipitate was thenfiltered, washed and dried in a vacuum oven at 50° C. for 24 hours togive Zoledronate disodium crystal form VI.

Total volume Y % of solution Sample X % EtOH or (H₂O/EtOH LOD by No. H₂OMeOH or MeOH) Yield (g/%) TGA 1 60% 40% EtOH 125 ml 4.9 g/86% 12.9% (75ml) (50 ml) 2 60% 40% MeOH 125 ml 4.5 g/78% 13.0% (75 ml) (50 ml)

Example 48

A solution of sodium hydroxide (1.4 g) in a mixture of water (80%v/v)/IPA (20% v/v, 10 volumes per grams of ZLD-Ac form I) (38 ml) wasadded drop-wise to a suspension of Zoledronic acid form I (5.0 g) in amixture of water (80% v/v)/IPA (20% v/v, 10 volumes per grams of ZLD-Ac)(212 ml) at reflux temperature. The reaction mixture was heated atreflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature and the solution was evaporated todryness. The obtained solid was dried in a vacuum oven at 50° C. for 5hours to give 5.2 g (78%) of Zoledronate disodium crystal form VI (LODby TGA=15.4%). Purity by HPLC 99.9%.

Example 49

Zoledronate disodium crystal form XIX (4.0 g) was dissolved in water (10ml) at reflux temperature. After about 30 minutes at reflux temperaturea precipitate was obtained. The suspension was then cooled to 0° C.using an ice-bath. The solid was isolated by filtration and dried in avacuum oven at 50° C. for 17 hours to give 2.0 g (50%) of Zoledronatedisodium crystal form VI.

Preparation of ZLD-Na₂ Crystal Form VII

Example 50

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometerand a reflux condenser was loaded with Zoledronic acid form I (10.0 g)and water (260 ml). The suspension was heated to 80° C. to obtain aclear solution. Sodium hydroxide (pearls, 2.84 g) was added. A pH testof the sodium salt showed pH=7.35. The solution was cooled to 60° C. andIPA (10.5 ml) was added. The reaction mixture was cooled to roomtemperature during 2 hours and was stirred at this temperature for about16 hours. After cooling to 5° C. and stirring at this temperature for 2hours, the solution was evaporated to dryness to obtain a white solid.The obtained solid was reslurried in water (50 ml) and cooled to 4° C.The product was then isolated by filtration and dried in a vacuum ovenat 50° C. for 24 hours to obtain 3.2 g of Zoledronate disodium crystalform VII (24%) (pH=7.27). Purity by HPLC 100.0%.

Example 51

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with Zoledronic acidform I (10.0 g) and water (130 ml). The suspension was heated to refluxtemperature to obtain a clear solution. A 40% aqueous solution of Sodiumhydroxide (6.9 g) was added drop-wise. The solution was then cooled to4° C. during 2 hours and was stirred at this temperature for about 1.5hours. The solution was concentrated to half of its volume to obtain aprecipitate. The white precipitate was filtered and dried in a vacuumoven at 50° C. for 22 hours to obtain 2.7 g (22%) of Zoledronatedisodium crystal form VII (LOD by TGA=10.7%).

Example 52

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with Zoledronic acidform I (10.0 g) and water (130 ml). The suspension was heated to refluxtemperature (92° C.) to obtain a clear solution. A 40% aqueous solutionof Sodium hydroxide (6.9 g) was added drop-wise. The solution was thencooled to 25° C. was stirred at this temperature for about 16 hours. Thesolution was then concentrated to half of its volume to obtain aprecipitate. The white precipitate was filtered and dried in a vacuumoven at 50° C. for 18.5 hours to obtain 2.8 g (23%) of Zoledronatedisodium crystal form VII (LOD by TGA=10.2%). Purity by HPLC 100.0%.

Example 53

A solution of sodium hydroxide (0.7 g) in a mixture of water (80%v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Acform XII) (38 ml) was added drop-wise to a suspension of Zoledronic acidform XII (4.98 g) in a mixture of water (80% v/v)/Ethanol or Methanol orIPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at refluxtemperature. The reaction mixture was heated at reflux temperature foradditional 16 hours. Then the reaction mixture was cooled to roomtemperature. Further cooling was performed using an ice-bath. Theprecipitate was then filtered, washed and dried in a vacuum oven at 50°C. for 24 hours to give Zoledronate disodium crystal form VII.

Total volume Y % of solution EtOH or (H₂O/EtOH Sample X % MeOH or orMeOH LOD by No. H₂O IPA or IPA) Yield (g/%) TGA 1 80% 20% EtOH 250 ml4.9 g/89% 9.2% (200 ml) (50 ml) 2 80% 20% MeOH 250 ml 4.5 g/83% 7.6%(200 ml) (50 ml) 3 80% 20% IPA 250 ml 4.7 g/85% 10.3%  (200 ml) (50 ml)

Example 54

A solution of sodium hydroxide (0.7 g) in a mixture of water (60%v/v)/IPA (40% v/v, 10 volumes per grams of ZLD-Ac form XII) (19 ml) wasadded drop-wise to a suspension of Zoledronic acid form XII (4.98 g) ina mixture of water (60% v/v)/IPA (40% v/v, 10 volumes per grams ofZLD-Ac) (106 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with IPA (1×20 ml)and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronatemonosodium crystal form VIII (crop I). Then the precipitate from themother-liquid was isolated by filtration as well, and dried in a vacuumoven at 50° C. for 24 hours to give 2.8 g (13%) of Zoledronate disodiumcrystal form VII (crop II).

Example 55

A solution of sodium hydroxide (1.4 g) in a mixture of water (80%v/v)/Ethanol (20% v/v, 10 volumes per grams of ZLD-Ac form I) (38 ml)was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) ina mixture of water (80% v/v)/Ethanol (20% v/v, 10 volumes per grams ofZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 18.5 hours. Then the reactionmixture was cooled to room temperature and the solution was evaporatedto dryness to obtain 6.7 g (98%) of Zoledronate disodium crystal formVII (LOD by TGA=16.8%). Purity by HPLC 99.9%.

Preparation of ZLD-Na₂ Crystal Form X

Example 56

A solution of sodium hydroxide (0.7 g) in a mixture of water (20%v/v)/IPA (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10 ml) wasadded drop-wise to a suspension of Zoledronic acid form XII (4.98 g) ina mixture of water (20% v/v)/IPA (80% v/v, 10 volumes per grams ofZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with IPA (1×25 ml)and dried in a vacuum oven at 50° C. for 24 hours to give 4.7 g (91%) ofZoledronate disodium crystal form X (LOD by TGA=2.6%).

Preparation of ZLD-Na₂ Crystal Form XIII

Example 57

A solution of sodium hydroxide (1.4 g) in a mixture of water (5%v/v)/Ethanol (95% v/v, 10 volumes per grams of ZLD-Ac form I) (8 ml) wasadded drop-wise to a suspension of Zoledronic acid form I (5.0 g) in amixture of water (5% v/v)/Ethanol (95% v/v, 10 volumes per grams ofZLD-Ac) (45 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 19.5 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed withEthanol (1×10 ml) and dried in a vacuum oven at 50° C. for 20 hours togive 4.9 g (84%) of Zoledronate disodium crystal form XIII (LOD byTGA=3.4%). Purity by HPLC 99.9%.

Preparation of ZLD-Na₂ Crystal Form XIV

Example 58

A solution of sodium hydroxide (0.7 g) in a mixture of water (20%v/v)/DMF (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10 ml) wasadded drop-wise to a suspension of Zoledronic acid form XII (4.98 g) ina mixture of water (20% v/v)/DMF (80% v/v, 10 volumes per grams ofZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 16 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with DMF (2×10 ml)and dried in a vacuum oven at 50° C. for 24 hours to give 4.8 g (92%) ofZoledronate disodium crystal form XIV (LOD by TGA=1.9%).

Example 59

A solution of sodium hydroxide (1.4 g) in a mixture of water (20%v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac form I) (10 ml)was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) ina mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams ofZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 17 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The precipitate was then filtered, washed with Methanol (1×10ml) and dried in a vacuum oven at 50° C. for 26 hours to give 5.6 g(97%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.4%). Purityby HPLC 99.9%.

Preparation of ZLD-Na₂ Crystal Form XIX

Example 60

Zoledronate disodium crystal form VII (1.0 g) was dissolved in water (19ml) at reflux temperature. After about 30 minutes at reflux temperaturea light precipitate was obtained. The suspension was then cooled to 0°C. using an ice-bath and was concentrated under vacuum to obtain amassive precipitation. The solid was isolated by filtration afterfurther stirring at 0° C., and dried in a vacuum oven at 50° C. for 27hours to give 0.4 g (40%) of Zoledronate disodium crystal form XIX.

Example 61

A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, areflux condenser and a dropping funnel, was loaded with Zoledronic acidform I (20.0 g) and water (260 ml). The suspension was heated to refluxtemperature (92° C.) to obtain a clear solution. A 40% aqueous solutionof Sodium hydroxide (13.8 g) was added drop-wise. The solution was thencooled to 25° C. and was stirred at this temperature for about 16 hours.The solution was then concentrated to half of its volume to obtain aprecipitate. After stirring at 0° C. for 72 hours, the white precipitatewas filtered and dried in a vacuum oven at 50° C. for 23 hours to obtain10.4 g of Zoledronate disodium crystal form XIX.

Preparation of ZLD-Na₂ Crystal Form XXV

Example 62

A solution of sodium hydroxide (1.4 g) in a mixture of water (80%v/v)/Methanol (20% v/v, 10 volumes per grams of ZLD-Ac form I) (38 ml)was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) ina mixture of water (80% v/v)/Methanol (20% v/v, 10 volumes per grams ofZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heatedat reflux temperature for additional 19 hours. Then the reaction mixturewas cooled to room temperature. Further cooling was performed using anice-bath. The solution was then evaporated to dryness to obtain 6.1 g(99%) of Zoledronate disodium crystal form XXV (LOD by TGA=7.4%). Purityby HPLC 99.9%.

Preparation of ZLD-Na₂ Crystal Form XXVII

Example 63

A 100 ml flask was loaded with Zoledronic acid form I (4.9 g), Sodiumhydroxide (1.4 g), Methanol (50 ml) and water (2.5 ml) [=5% v/v water inMethanol]. The reaction mixture was heated to reflux temperature for 21hours. Then the reaction mixture was cooled to room temperature. Furthercooling was performed using an ice-bath. The precipitate was thenfiltered, washed with absolute Ethanol (2×75 ml) and dried in a vacuumoven at 50° C. for 27.5 hours to give 5.7 g (93%) of Zoledronatedisodium crystal form XXVII (LOD by TGA=5.3%). Purity by HPLC 99.9%.

Example 64

A solution of sodium hydroxide (0.7 g) in a mixture of water (20%v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10 ml)was added drop-wise to a suspension of Zoledronic acid form XII (4.98 g)in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per gramsof ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture washeated at reflux temperature for additional 16 hours. Then the reactionmixture was cooled to room temperature. Further cooling was performedusing an ice-bath. The precipitate was then filtered, washed withMethanol (2×15 ml) and dried in a vacuum oven at 50° C. for 24 hours togive 4.85 g (90%) of Zoledronate disodium crystal form XXVII (LOD byTGA=7.5%).

Crystal Forms of Zoledronate Trisodium (ZLD-Na₃)

Preparation of ZLD-Na₃ Crystal Form IX

Example 65

A solution of sodium hydroxide (1.4 g) in a mixture of water (20%v/v)/Ethanol or Methanol or IPA (80% v/v, 10 volumes per grams of ZLD-Acform XII) (10 ml) was added drop-wise to a suspension of Zoledronic acidform XII (5.0 g) in a mixture of water (20% v/v)/Ethanol or Methanol orIPA (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at refluxtemperature. The reaction mixture was heated at reflux temperature foradditional 16 hours. Then the reaction mixture was cooled to roomtemperature. Further cooling was performed using an ice-bath. Theprecipitate was then filtered, washed and dried in a vacuum oven at 50°C. for 24 hours to give Zoledronate trisodium crystal form IX.

Total volume Y % EtOH of solution Sample or MeOH (H₂O/EtOH or Yield LODby No. X % H₂O or IPA MeOH or IPA) (g/%) TGA 1 20% 80% EtOH 63 ml 5.6g/84% 13.6% (13 ml) (50 ml) 2 20% 80% MeOH 63 ml 5.9 g/88% 13.7% (13 ml)(50 ml) 3 20% 80% IPA 63 ml 5.6 g/85% 13.5% (13 ml) (50 ml)

Example 66

A solution of sodium hydroxide (1.4 g) in a mixture of water (40%v/v)/Ethanol or Methanol or IPA (60% v/v, 10 volumes per grams of ZLD-Acform XII) (13 ml) was added drop-wise to a suspension of Zoledronic acidform XII (5.0 g) in a mixture of water (40% v/v)/Ethanol or Methanol orIPA (60% v/v, 10 volumes per grams of ZLD-Ac) (71 ml) at refluxtemperature. The reaction mixture was heated at reflux temperature foradditional 16 hours. Then the reaction mixture was cooled to roomtemperature. Further cooling was performed using an ice-bath. Theprecipitate was then filtered, washed and dried in a vacuum oven at 50°C. for 24 hours to give Zoledronate trisodium crystal form IX.

Total volume Y % EtOH of solution Sample or MeOH (H₂O/EtOH or Yield LODby No. X % H₂O or IPA MeOH or IPA) (g/%) TGA 1 40% 60% EtOH 83 ml 5.7g/68% 13.9% (33 ml) (50 ml) 2 20% 60% MeOH 83 ml 5.5 g — (33 ml) (50 ml)3 20% 60% IPA 83 ml 5.7 g/85% 14.3% (33 ml) (50 ml)

Example 67

A solution of sodium hydroxide (1.4 g) in a mixture of water (50%v/v)/Ethanol or Methanol or IPA (50% v/v, 10 volumes per grams of ZLD-Acform XII) (15 ml) was added drop-wise to a suspension of Zoledronic acidform XII (5.0 g) in a mixture of water (50% v/v)/Ethanol or Methanol orIPA (50% v/v, 10 volumes per grams of ZLD-Ac) (85 ml) at refluxtemperature. The reaction mixture was heated at reflux temperature foradditional 16 hours. Then the reaction mixture was cooled to roomtemperature. Further cooling was performed using an ice-bath. Theprecipitate was then filtered, washed and dried in a vacuum oven at 50°C. for 24 hours to give Zoledronate trisodium crystal form IX.

Total volume Y % EtOH of solution Sample or MeOH (H₂O/EtOH or Yield LODby No. X % H₂O or IPA MeOH or IPA) (g/%) TGA 1 50% 50% EtOH 100 ml 5.5g/84% 11.6% (50 ml) (50 ml) 2 50% 50% MeOH 100 ml 5.2 g/77% 14.6% (50ml) (50 ml) 3 50% 50% IPA 100 ml 5.3 g/85%  8.6% (50 ml) (50 ml)

Example 68

A solution of sodium hydroxide (1.4 g) in a mixture of water (60%v/v)/Ethanol or Methanol or IPA (40% v/v, 10 volumes per grams of ZLD-Acform XII) (19 ml) was added drop-wise to a suspension of Zoledronic acidform XII (5.0 g) in a mixture of water (60% v/v)/Ethanol or Methanol orIPA (40% v/v, 10 volumes per grams of ZLD-Ac) (106 ml) at refluxtemperature. The reaction mixture was heated at reflux temperature foradditional 16 hours. Then the reaction mixture was cooled to roomtemperature. Further cooling was performed using an ice-bath. Theprecipitate was then filtered, washed and dried in a vacuum oven at 50°C. for 24 hours to give Zoledronate trisodium crystal form IX.

Total volume Y % EtOH of solution Sample or MeOH (H₂O/EtOH or Yield LODby No. X % H₂O or IPA MeOH or IPA) (g/%) TGA 1 60% 40% EtOH 125 ml 5.1g/58% 16.8% (75 ml) (50 ml) 2 60% 40% MeOH 125 ml 4.1 g/64% 11.8% (75ml) (50 ml) 3 60% 40% IPA 125 ml 5.3 g/79% 14.1% (75 ml) (50 ml)

Example 69

A solution of sodium hydroxide (1.4 g) in a mixture of water (80%v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Acform XII) (38 ml) was added drop-wise to a suspension of Zoledronic acidform XII (5.0 g) in a mixture of water (80% v/v)/Ethanol or Methanol orIPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at refluxtemperature. The reaction mixture was heated at reflux temperature foradditional 16 hours. Then the reaction mixture was cooled to roomtemperature. Further cooling was performed using an ice-bath. Theprecipitate was then filtered, washed and dried in a vacuum oven at 50°C. for 24 hours to give Zoledronate trisodium crystal form IX.

Total volume Y % EtOH of solution Sample or MeOH (H₂O/EtOH or Yield LODby No. X % H₂O or IPA MeOH or IPA) (g/%) TGA 1 80% 20% EtOH 250 ml 5.7g/84% 15.1% (200 ml) (50 ml) 2 80% 20% MeOH 250 ml 5.6 g/86% 12.4% (200ml) (50 ml) 3 80% 20% IPA 250 ml 5.6 g/83% 14.5% (200 ml) (50 ml)Preparation of ZLD-Na₃ Crystal Form XI

Example 70

A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodiumhydroxide (1.4 g), absolute Ethanol (50 ml) and water (2.5 ml) [=5% v/vwater in Ethanol]. The reaction mixture was heated to reflux temperaturefor 20 hours. Then the reaction mixture was cooled to room temperature.Further cooling was performed using an ice-bath. The precipitate wasthen filtered, washed with absolute Ethanol (2×25 ml) and dried in avacuum oven at 50° C. for 24 hours to give 5.4 g (86%) of Zoledronatetrisodium crystal form XI (LOD by TGA=8.9%).

Example 71

A 250 ml flask was loaded with Zoledronic acid form XII (5.0 g), Sodiumhydroxide (1.4 g), Methanol (50 ml) and water (2.5 ml) [=5% v/v water inMethanol]. The reaction mixture was heated to reflux temperature for 22hours. Then the reaction mixture was cooled to room temperature. Furthercooling was performed using an ice-bath. The precipitate was thenfiltered, washed with Methanol (2×50 ml) and dried in a vacuum oven at50° C. for 24 hours to give 5.4 g (84%) of Zoledronate trisodium crystalform XI in a mixture with crystal form IX (LOD by TGA=10.5%).

General Procedure for the Preparation of Amorphous Zoledronate Sodium

Example 72

A 100 ml flask was loaded with Zoledronic acid crystal form XII (2.0 g),Sodium hydroxide (0.57 g) and water (10 ml). The reaction mixture wasstirred at room temperature to obtain a clear solution. Then thesolution was concentrated under vacuum to obtain a precipitate. Furthercooling was performed using an ice-bath. The precipitate was thenfiltered, washed with water (2×10 ml) and dried in a vacuum oven at 50°C. for 24 hours to give 0.76 g of amorphous Zoledronate sodium.

Summarizing Tables—Crystals Forms of Zoledronate Sodium Salts

1. Preparation of Zoledronate monosodium salt: EtOH MeOH IPA  0% v/v H₂OI (ZLD-Ac) + XV(ZLD-Ac) XV(ZLD-Ac) No reaction 20% v/v H₂O XII(ZLD-Ac) >IV 50% v/v H₂O XVI No reaction XVI 80% v/v H₂O VIII >> XII(ZLD-Ac) VIIIVIII Using ZLD-Ac (assay 100%, Form I) as a starting material

2. Preparation of Zoledronate disodium salt: EtOH MeOH IPA  5% v/v H₂OXIII XXVII No reaction 20% v/v H₂O V XIV V 50% v/v H₂O V > VI + IX V >>IX? V 80% v/v H₂O VII XXV VI Using ZLD-Ac (assay 100%, Form I) as astarting material EtOH MeOH IPA DMF  20% v/v H₂O V V + XXVII X XIV  40%v/v H₂O V V > XII V =  50% v/v H₂O V V > VIII V > VIII =  60% v/v H₂O VIVI + 11.3 VIII (crop I) = VII + 8.2 (crop II)  80% v/v H₂O VII VII VII +8.2, 9.1 — 100% v/v H₂O Amorphous Using ZLD-Ac (assay 90%, Form XII) asa starting material

3. Preparation of Zoledronate trisodium salt: EtOH MeOH IPA  5% v/v H₂OXI IX + XI —  20% v/v H₂O IX + IV IX > IV + 9.9 IX + 6.4, 6.7  40% v/vH₂O IX IX + V IX + IV  50% v/v H₂O IX + IV IX + V >> IV IX + IV +amorph. + 7.1  60% v/v H₂O IX + IV IX > IV IX  80% v/v H₂O IX IX IX 100%v/v H₂O Amorphous Using ZLD-Ac (assay 90%, Form XII) as a startingmaterial

1. Crystalline solid zoledronic acid (Form XII) characterized by apowder X-ray pattern having peaks at 9.0°, 13.9°, 14.8°, 21.5°, 24.7°,and 29.8° 2θ±0.2° 2θ.
 2. The crystalline zoledronic acid of claim 1,further characterized by a powder X-ray diffraction pattern with peaksat 17.0°, 20.6°, 20.8°, 22.4°, 25.8°, 27.7°, 28.4°, 28.7°, 29.1°, 30.8°,31.9°, 32.3°, and 32.9° 2θ±0.2° 2θ.